Fungicidal 2-pyridyl alkyl amides and their compositions, methods of use and preparation

ABSTRACT

The present invention relates to compounds of Formula I: 
                 
 
wherein: 
                 
 
represents a 6-membered heterocyclic aromatic ring in which X 1  is N, and X 2 , X 3  and X 4  are CR″;
         wherein R″ is independently H, halogen, cyano, hydroxy, C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, cyclopropyl, C 1 -C 3  alkoxy, C 1 -C 3  haloalkoxy, C 1 -C 3  alkylthio, aryl, C 1 -C 3  NHC(O)alkyl, NHC(O)H, C 1 -C 3  haloalkylthio, C 2 -C 4  alkenyl, C 2 -C 4  haloalkenyl, C 2 -C 4  alkynyl, C 2 -C 4  haloalkynyl or nitro wherein adjacent R″ substituents may form a ring;   b) Z is O, S or NOR z  in which R z  is H or C 1 -C 3  alkyl; and   c) A represents
           (i) C 2 -C 14  alkenyl, or C 2 -C 14  alkynyl, all of which may be branched or unbranched, unsubstituted or substituted with halogen, hydroxy, nitro, aroyl, aryloxy, C 1 -C 8  acyloxy, C 1 -C 6  alkylthio, arylthio, aryl, heteroaryl, heteroarylthio, heteroaryloxy, C 1 -C 6  acyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy or C 1 -C 6  haloalkoxy, and   (ii) C 3 -C 14  cycloalkyl, containing 0 heteroatoms and 0-2 unsaturations, substituted with aryloxy, heteroaryloxy, C 1 -C 6  alkylthio, arylthio, heteroarylthia, C 1 -C 6  alkoxy, or C 1 -C 6  haloalkoxy;
 
which are useful as antifungal agents, particularly for plants.

PRIORITY CLAIM

This application is a divisional of, and claims the priority of,application Ser. No. 09/620,662, now granted as U.S. Pat. No. 6,521,622,which has a filing date of Jul. 20, 2000, and which claims the priorityof provisional application No. 60/144,676, which has a filing date ofJul. 20, 1999, the entire disclosures of both are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the field of fungicidal compositionsand methods. More particularly, the present invention concerns novelfungicidal heterocyclic aromatic amides and methods involvingapplication of fungicidally effective amounts of such compounds to thelocus of a plant pathogen. The present invention also concerns methodsuseful in the preparation of heterocyclic aromatic amides and theirfungicidal compositions.

2. Description of the Prior Art

A variety of antifungal compositions and methods are well known in theart. Antimycin, for example, has been identified as a naturallyoccurring substance produced by Streptomyces spp. with antibioticproperties (Barrow, C. J.; et al., Journal of Antibiotics, 1997, 50(9),729). These substances have also been found to be effective fungicides(The Merck Index, Twelfth Edition, S. Budavari, Ed., Merck and Co.,Whitehouse Station, N.J., 1996, p.120). WO 97/08135 describesacylaminosalicylic acid amides which are useful as pesticides.EP-A-O-661269 discloses substituted heterocyclic carboxylic acid amidesuseful as medical drugs. JP-A-7-233165 discloses antifungal dilactoneshaving 3-hydroxypyridinecarboxyl groups with antimycotic action. Theiso-butyryl, tigloyl, iso-valeryl and 2-methylbutyryl derivatives ofthese latter compounds are further described in the followingreferences: Tetrahedron 1998, 54, 12745-12774; J. Antibiot. 1997, 50(7),551; J. Antibiot. 1996, 49(7), 639; J. Antibiot. 1996, 49(12), 1226; andTetrahedron Lett. 1998, 39, 4363-4366.

However, there has remained a need for new fungicides. The presentinvention provides fungicides which have a high residual activity,greater activity at lower application rates, curative activity, and abroader spectrum of efficacy.

SUMMARY OF THE INVENTION

Briefly describing one aspect of the present invention, there areprovided compounds comprising heterocyclic aromatic amides (HAA) of theFormula I;

wherein X₁-X₄, Z, and A are hereafter defined. The invention alsoencompasses hydrates, salts and complexes thereof.

The present invention also provides fungicidal compositions comprisingthe HAA in combination with phytologically acceptable carriers and/ordiluents. Methods for the use of the heterocyclic aromatic amidecompounds and compositions are also disclosed.

It is an object of the present invention to provide HAA and compositionsthereof which are effective as antifungal agents.

Another object of the present invention is to provide methods for thecontrol and/or prevention of fungal infestations, which methods includethe application of HAA and compositions containing same.

Further objects and advantages of the present invention will be apparentfrom the description which follows.

GENERAL SCOPE OF THE INVENTION

The present invention relates to various HAA compounds which are activeas antifungal agents. Also included are formulations including the HAAcompounds, and methods of using the HAA compounds and formulations. Themethods of preparing the HAA compounds are also encompassed by thepresent invention and their method of preparation and use as fungicides.

HAA Compounds

The novel antifungal HAA compounds of the present invention aredescribed by the following Formula I:

wherein:

-   -   a.        represents a 5- or 6-membered heterocyclic aromatic ring in        which        -   (i) each of X₁-X₄ is independently O, S, NR′, N, CR″ or a            bond;        -   (ii) no more than one of X₁-X₄ is O, S or NR′;        -   (iii) no more than one of X₁-X₄ is a bond;        -   (iv) when any one of X₁-X₄ is S, O or NR′, one of the            adjacent X₁-X₄ must represent a bond; and        -   (v) at least one of X₁-X₄ must be O, S, NR′ or N; wherein            -   R′ is H, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl,                hydroxy, acyloxy, C₁-C₆ alkoxymethyl, CHF₂, cyclopropyl                or C₁-C₄ alkoxy; and R″ is independently H, halogen,                cyano, hydroxy, C₁-C₃ alkyl, C₁-C₃ haloalkyl,                cyclopropyl, C₁-C₃ alkoxy, C₁-C₃ haloalkoxy, C₁-C₃                alkylthio, aryl, C₁-C₃ NHC(O)alkyl, NHC(O)H, C₁-C₃                haloalkylthio, C₂-C₄ alkenyl, C₂-C₄ haloalkenyl, C₂-C₄                alkynyl, C₂-C₄ haloalkynyl or nitro wherein adjacent R″                substituents may form a ring or adjacent R′ and R″                substituents may form a ring;    -   b) Z is O, S or NOR_(z) in which R_(z) is H or C₁-C₃ alkyl; and    -   c) A represents        -   (i) C₁-C₁₄ alkyl, C₂-C₁₄ alkenyl, or C₂-C₁₄ alkynyl, all of            which may be branched or unbranched, unsubstituted or            substituted with halogen, hydroxy, nitro, aroyl, aryloxy,            C₁-C₈ acyloxy, C₁-C₆ alkylthio, arylthio, aryl, heteroaryl,            heteroarylthio, heteroaryloxy, C₁-C₆ acyl, C₁-C₆ haloalkyl,            C₁-C₆ alkoxy or C₁-C₆ haloalkoxy,        -   (ii) C₃-C₁₄ cycloalkyl, containing 0-3 heteroatoms and 0-2            unsaturations, which may be unsubstituted or substituted            with halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, cyano,            nitro, aroyl, aryloxy, heteroaryloxy, C₁-C₆ alkylthio,            arylthio, heteroarylthio, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,            C₁-C₈ acyloxy, aryl, heteroaryl, C₁-C₆ acyl, carboaryloxy,            carboheteroaryloxy, C₁-C₆ carboalkoxy or amido unsubstituted            or substituted with one or two C₁-C₆ alkyl groups,        -   (iii) C₆-C₁₄ bi- or tricyclic ring system, containing 0-3            heteroatoms and 0-2 unsaturations, which may be            unsubstituted or substituted with halogen, hydroxy, C₁-C₆            alkyl, C₁-C₆ haloalkyl, cyano, nitro, aroyl, aryloxy,            heteroaryloxy, C₁-C₆ alkylthio, arylthio, heteroarylthio,            C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₈ acyloxy, aryl,            heteroaryl, C₁-C₆ acyl, carboaryloxy, carboheteroaryloxy,            C₁-C₆ carboalkoxy or amido unsubstituted or substituted with            one or two C₁-C₆ alkyl groups,        -   (iv) aryl or heteroaryl, which may be unsubstituted or            substituted with nitro, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆            cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, heteroaryl,            halogen, hydroxy, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,            carboaryloxy, carboheteroaryloxy, C₁-C₆ carboalkoxy or amido            unsubstituted or substituted with one or two C₁-C₆ alkyl            groups, C₁-C₆ alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆            alkylsulfinyl, C₁-C₆ OC(O)alkyl, OC(O)aryl, C₃-C₆            OC(O)cycloalkyl, C₁-C₆ NHC(O)alkyl, C₃-C₆ NHC(O)cycloalkyl,            NHC(O)aryl, NHC(O)heteroaryl, C₃-C₆ cycloalkylthio, C₃-C₆            cycloalkylsulfonyl, C₃-C₆ cycloalkylsulfinyl, aryloxy,            heteroaryloxy, heteroarylthio, heteroarylsulfinyl,            heteroarylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl,            C(O)R_(Y), C(NOR_(X))R_(Y), in which any alkyl or cycloalkyl            containing substituent may be substituted with one or more            halogens and in which any aryl or heteroaryl containing            substituent may also be unsubstituted or substituted with            halogen, cyano, nitro, aroyl, aryloxy, aryl, heteroaryl,            C₁-C₆ acyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,            C₁-C₆ carboalkoxy or amido unsubstituted or substituted with            one or two C₁-C₆ alkyl groups, where R_(Y) and R_(X) are            independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆            cycloalkyl, aryl or heteroaryl, and            where *=point of attachment            in which    -   Q₁, Q₂ are O or S;    -   W is O, CH₂, CHR₆, or a bond;    -   R₁ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈        cycloalkyl, aryl or heteroaryl;    -   R₂ is H, C₁-C₃ alkyl, C₂-C₅ alkenyl or C₂-C₅ alkynyl;    -   R₃ is H, R₁, OR₁, OC(O)R₁, OC(O)OR₁ or OC(O)NR₁R₆;    -   R₄ and R₅ are independently H, C₁-C₆ alkyl, or C₂-C₆ alkenyl,        provided that the sum of carbons for R₄ plus R₅ is six or less,        and further provided that R₄ and R₅ may be joined into a C₃-C₆        ring;    -   R6 and R7 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl,        C2-C5 alkenyl or C2-C5 alkynyl provided that at least one of R6        and R7 is H;    -   with the proviso that when    -   wherein    -   R″ is H or OCH₃, then    -   R₁ is not C₁-C₈ alkyl or C₂-C₈ alkenyl.

The terms alkyl, alkenyl, alkynyl and the like, as used herein, includewithin their scope both straight and branched groups; the terms alkenyl,alkenylene and the like are intended to include groups containing one ormore double bonds; and the terms alkynyl, alkynylene and the like areintended to include groups containing one or more triple bonds.Cycloalkyl, as used herein, refers to C₃-C₁₄ cycloalkyl groupscontaining 0-3 heteroatoms and 0-2 unsaturations. Bi- or tricyclic ringsystems refers to C₆-C₁₄ aliphatic ring systems containing 0-3heteroatoms and 0-2 unsaturations. The foregoing terms furthercontemplate either substituted or unsubstituted forms. Unlessspecifically defined otherwise, a substituted form refers tosubstitution with one or more groups selected from halogen, hydroxy,cyano, nitro, aroyl, aryloxy, aryl, arylthio, heteroaryl, heteroaryloxy,heteroarylthio, C₁-C₈ acyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, carboaryloxy,carboheteroaryloxy, C₁-C₆ carboalkoxy or amido unsubstituted orsubstituted with one or two C₁-C₆ alkyl groups. All of the above termsand definitions assume that the rules of chemical bonding and strainenergy are satisfied.

The term aryl as used herein refers to a substituted phenyl or naphthylgroup. The term heteroaryl refers to any 5 or 6 membered aromatic ringcontaining one or more heteroatoms; these heteroaromatic rings may alsobe fused to other aromatic systems. The foregoing terms furthercontemplate either substituted or unsubstituted forms. A substitutedform refers to substitution with one or more groups selected from nitro,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, aryl, heteroaryl, halogen, hydroxy, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylsulfinyl,C₁-C₆ OC(O)alkyl, OC(O)aryl, C₃-C₆ OC(O)cycloalkyl, C₁-C₆ NHC(O)alkyl,C₃-C₆ NHC(O)cycloalkyl, NHC(O)aryl, NHC(O)heteroaryl, C₃-C₆cycloalkylthio, C₃-C₆ cycloalkylsulfonyl, C₃-C₆ cycloalkylsulfinyl,aryloxy, heteroaryloxy, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, C(O)R_(Y),C(NOR_(X))R_(Y) where R_(Y) and R_(X) are independently H, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, aryl or heteroaryl in which any alkylor cycloalkyl containing substituent may be substituted with one or morehalogens and provided that the rules of chemical bonding and strainenergy are satisfied.

The terms halogen and halo as used herein include chlorine, bromine,fluorine and iodine. The terms haloalkyl and the like refer to groupssubstituted with one or more halogen atoms.

The term Me as used herein refers to a methyl group. The term Et refersto an ethyl group. The term Pr refers to a propyl group. The term Burefers to a butyl group. The term EtOAc refers to ethyl acetate.

The term alkoxy as used herein refers to a straight or branched chainalkoxy group. The term haloalkoxy refers to an alkoxy group substitutedwith one or more halogen atoms.

The term heteroatom as used herein refer to O, S and N.

The preferred 5- or 6-membered heterocyclic aromatic rings of theformula

include the appropriate isomers of pyridine, pyridazine, pyrimidine,pyrazine, pyrrole, pyrazole, imidazole, furan, thiophene, oxazole,isoxazole, thiazole, isothiazole, and thiadiazole. The most preferredheterocyclic aromatic rings are pyridine, pyrimidine, pyrazine,pyridazine, thiazole, isothiazole, and oxazole. Particularly preferredcompounds of Formula I are based upon 2-amido-3-hydroxypyridine,2-amido-3-hydroxy-4-methoxypyridine, 2-amido-3-hydroxypyrazine, and4-amido-5-hydroxypyrimidine.

It will be appreciated that certain combinations of substituent groupsfor compounds which fall within the definitions given herein will beimpossible to prepare for steric and/or chemical reasons. Such compoundsare not included within the scope of the invention.

Various hydrates, salts and complexes of compounds of Formula I can bemade in the conventional ways. For example, salts may be formed byreplacing the hydroxyl hydrogen atom with a cation, for example NH₄ ⁺,⁺N(Bu)₄, K⁺, Na⁺, Ca²⁺, Li⁺, Mg²⁺, Fe²⁺, Cu²⁺, etc. These derivativesare also useful in accordance with the present invention.

Throughout this document, all temperatures are given in degrees Celsius(° C.) and all percentages are weight percentages, unless otherwisestated. The term ppm refers to parts per million. The term psi refers topounds per square inch. The term m.p. refers to melting point. The termb.p. refers to boiling point.

Preparation of Compounds

The compounds of this invention are made using well known chemicalprocedures. The required starting materials are commercially availableor readily synthesized utilizing standard procedures.

Genereal Preparation of Pyridine-2-carboxamides.

The desired HAAs (2) are prepared by reacting the appropriateortho-hydroxyheteroaromatic carboxylic acid (1) with an amine in thepresence of a coupling reagent (phosgene or1-[3-dimethylaminopropyl]-3-ethylcarbodiimide hydrochloride [EDCI]) plus1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) andan acid scavenger, e.g. N-methylmorpholine (NMM), triethylamine,4-(dimethylamino)pyridine (DMAP), or diisopropylethylamine) (Scheme 1).In some cases acid chlorides with protected hydroxy groups such as (3)could be reacted with the appropriate amine to give the intermediateamides (4). Removal of the protecting groups via hydrogenation in thepresence of a palladium (Pd) catalyst gives the desired product (2X).

Preparation of the Ortho-hydroxyheteromatic Carboxylic Acids 1.

Preparation of carboxylic acids 1 (X₁=N, X₂=X₃=CH, X₄=independentlyC-Me, C—SMe, C—Cl) is shown in Scheme 2. Reaction of3-hydroxy-2-bromopyridine (5) with 2-(trimethylsilyl)ethoxymethylchloride (SEM-Cl) using potassium tert-butoxide as the base in a 1:1mixture of dimethylformamide (DMF)-tetrahydrofuran (THF) gave thedesired ether 6. Deprotonation of 6 with lithium diisopropylamide (LDA)followed by condensation with the appropriate electrophile (iodomethane,dimethyldisulfide, or hexachloroethane) gave the 4-substituted pyridine7. Bromine/lithium exchange between 7 and n-butyllithium (n-BuLi)followed by carboxylation with carbon dioxide (CO₂) and acid hydrolysisgave the necessary 4-substituted-3-hydroxypicolinic acid 1X.

Alternatively, 3-hydroxypyridine (8) could be condensed with SEM-Cl togive 9 (Scheme 3). Deprotonation of 9 with tert-butyllithium (t-BuLi)followed by condensation with N-fluorobenzensulfonimide gave the4-fluoro derivative 10. Condensation of 10 with sodium ethoxide gave thediether 11. Deprotonation of 11 with t-BuLi followed by carboxylationand acid hydrolysis gave the desired 4-ethoxypyridine 1X (X=OEt).

The preparation of acid chloride 3 is outlined in Scheme 4. Thus,3-hydroxypicolinic acid (12) was converted to the methyl ester 13 inrefluxing methanol using boron trifluoride as catalyst. 13 was thenbrominated using bromine in aqueous base to give the dibromide 14. Thebenzyl ether 15 was then prepared by condensation of 14 with benzylchloride in the presence of sodium hydride. Careful methanolysis of 15in methanol/potassium carbonate gave the 4-methoxypicolinic acidderivative 16. Conversion of 16 to the acid chloride 3 was accomplishedwith oxalyl chloride using benzene as a solvent and a catalytic amountof DMF.

Preparation of 4-Ethoxy-3-hydroxypicolinic Acid (1, X₁=N, X₂=X₃=H,X₄=COEt) (See Schemes 1 and 3).

a. Preparation of 3-(2-(Trimethylsilyl)ethoxymethoxymethoxy)pyridine(9).

To a stirred mixture of DMF (100 mL) and THF (100 mL), was added solidpotassium tert-butoxide (17.96 g, 0.16 mol). After all of the solid haddissolved, the solution was cooled to ≦5° C. and 3-hydroxypyridine(14.25 g, 0.15 mol) was added all at once. After stirring for 10minutes, the mixture was cooled to −10° C. and SEM-Cl, 25 g, 0.15 mol)was added dropwise at such a rate that the internal temperature remainedat ≦−5° C. After the addition was complete, the mixture was stirred at0° C. for 1 hour, then at room temperature for 2 hours. The mixture waspoured into water (600 mL), then extracted with ether (3×150 mL). Theether extracts were combined, washed sequentially with 2N NaOH (100 mL),water (50 mL), and saturated NaCl solution (100 mL), dried (MgSO₄) andconcentrated to give a brown liquid. Distillation gave the desired ether9 as a colorless liquid (20.8 g), b.p. 95-99° C. @ 0.03 mm Hg.

b. Preparation of 4-Fluoro-3-(2-(trimethylsilyl)ethoxymethoxy)pyridine(10).

To a stirred solution of 9 (12.39 g, 0.055 mol) in ether (200 mL) cooledto ≦−70° C. under an atmosphere of argon was slowly added t-BuLi (40 mL,1.5 M pentane solution). During the addition, the reaction temperaturewas maintained at ≦−68° C. After the addition was complete the mixturewas stirred an additional 60 minutes at ≦−70° C., then transferred viacannula to a stirred solution of N-fluorobenzenesulfonimide (18.92 g) indry THF (200 mL) which was also cooled to ≦−70° C. under argon. Afterthe addition was complete, the cooling bath was removed and the reactionmixture was allowed to warm up to room temperature. Water (100 mL) wasadded and the organic phase was separated, dried (MgSO₄) andconcentrated to give a brown oil. Chromatography (silica gel,hexane-acetone, 9:1) gave the desired product 10 as an orange oil (7.5g) which contained about 15% starting material. This crude mixture wasused directly in the next reaction.

c. Preparation of 4-Ethoxy-3-(2-(trimethylsilyl)ethoxymethoxy)pyridine(11).

To a stirred solution of sodium ethoxide (0.9 g, 13 mmol) in ethanol (10mL) was added all at once 10 (1.07g, 4.4 mmol). The resulting mixturewas stirred at room temperature for 48 hours, then poured into water(100 mL). The resulting mixture was extracted with ether (3×50 mL). Theether extracts were combined, dried (MgSO₄) and concentrated. Theresulting amber oil was chromatographed (silica gel, hexane-acetone,4:1) to give 11 as a yellow oil (0.6 g).

d. 4-Ethoxy-3-hydroxypyridine-2-carboxylic Acid (1, X₁=N, X₂=X₃=CH,X₄=COEt).

A stirred solution of 11 (2.9 g) in THF (50 mL) under an argonatmosphere was cooled to ≦−70° C. To this was slowly added t-BuLi (8 mL,1.5M pentane solution) while keeping the reaction temperature at ≦−66°C. After the addition was complete, the mixture was stirred at ≦−70° C.for 45 minutes and then poured into a slurry of crushed dry ice inether. The resulting mixture was stirred until it reached roomtemperature, then the solvents were evaporated. THF (25 mL) and 4N HCl(15 mL) were added to the residue and the resulting mixture was stirredat room temperature for two hours. At the end of this period, theinsoluble material was filtered, washed with a small volume of THF andair dried to give the title compound as a white solid (1.05 g).Preparation of 6-Bromo-3-benzyloxy-4-methoxypyridine-2-carboxylic Acid(16) and its Acid Chloride (3) (See Scheme 4).

a. Preparation of Methyl 4,6-Dibromo-3-hydroxypyridine-2-carboxylate(14).

To a 2 L, 3-necked flask equipped with a dropping funnel and amechanical stirrer, was added water (800 mL) and methyl3-hydroxypyridine-2-carboxylate (15.3 g). To this stirred solution wasslowly added bromine (32 g). As the reaction progressed, a solidseparated from solution and the reaction mixture became difficult tostir. After the addition was complete, the mixture was vigorouslystirred until the bromine color disappeared. ¹H-NMR (CDCl₃) of a smallsample of the crude product showed that it was about a 3:1 mixture ofmono to dibrominated product. Sodium carbonate (31.8 g) was carefullyadded to the reaction mixture and then additional bromine (12 g) wasadded dropwise. After the bromine color had disappeared, the reactionmixture was adjusted to approximately pH 5 with conc. HCl, and theresulting mixture was extracted with CH₂Cl₂ (3×150 mL). The organicextracts were combined, dried (MgSO₄) and concentrated to give an orangesolid (14 g). This material could be recrystallized frommethylcyclohexane (after charcoal treatment) to give 14 as a whitesolid, m.p. 181-183° C.

b. Preparation of Methyl 4,6-Dibromo-3-benzyloxypyridine-2-carboxylate(15).

To a stirred mixture of sodium hydride (0.6 g) in DMF (50 mL) was slowlyadded 14 (7.1 g). After the addition was complete, the mixture wasstirred at room temperature for 15 minutes, then benzyl chloride (3.05g) was added all at once. The mixture was then heated at 90° C. for sixhours, cooled, poured into water (500 mL) and extracted with ether(2×200 mL). The ether extracts were combined, washed with 2N NaOH (50mL), dried (MgSO₄) and the solvent was evaporated to give 15 as a lightyellow solid (8.3 g). Recrystallization from a small volume of methanolgave an analytical sample, m.p. 75-76° C.

c. 6-Bromo-3-benzyloxy-4-methoxypyridine-2-carboxylic Acid (16).

A vigorously stirred mixture of 15 (25.5 g), potassium carbonate (75 g)and methanol (300 mL) was heated at reflux for 30 hours. The mixture wascooled, poured into water (800 mL), and the pH adjusted to 2 by theaddition of conc. HCl. The resulting mixture was extracted with CH₂Cl₂(3×150 mL). The organic extracts were combined, dried (MgSO₄) and thesolvent was evaporated to give a nearly colorless oil (20.5 g) whichslowly solidified upon standing. This was recrystallized from methanol(125 mL)/water (40 mL) to give the desired acid 16 (11.6 g), m.p.134-135° C.

d. Preparation of 6-Bromo-3-benzyloxy-4-methoxypyridine-2-carbonylChloride (3).

To a stirred mixture of 16 (2.54 g., 7.5 mmol) in benzene (30 mL)containing DMF (3 drops) was added oxalyl chloride (1.90 g, 15 mmol) inone portion. After gas evolution had ceased (about 45 min.), the nowhomogeneous solution was stirred an additional 15 min., then the solventwas evaporated. 1,2-dichloroethane (30 mL) was added and again thesolvent was evaporated to give a quantitative yield of 3 as a nearlycolorless oil. This material was dissolved in CH₂Cl₂ (10 mL) or THF (10mL) and used directly in subsequent coupling reactions.6-Bromo-3-hydroxypicolinic Acid (17).

To a mechanically stirred solution of methyl 3-hydroxypicolinate (30.6g) in water (800 mL) was slowly added bromine (32 g) over a 30 minuteperiod. After the addition was complete, stirring was continued for anadditional hour. Ether (300 mL) was added and stirring continued untilall the solids had dissolved. The organic layer was separated and theaqueous phase extracted with ether (200 mL). The organic phases werecombined, dried (MgSO₄) and the solvent evaporated to give 32.8 g ofmethyl 6-bromo-3-hydroxypicolinate as an off-white solid.Recrystallization from methanol/water gave an analytical sample, m.p.115-117° C.

To a stirred solution of this ester (2.32 g) in THF (15 mL) was addedall at once a solution of LiOH.H₂O (1 g) in water (7 mL). The resultingmixture was stirred for 2 hours at room temperature then poured intowater (100 mL). The pH was adjusted to approximately 3 with 1N HCl, thenthe mixture was extracted with CH₂Cl₂ (3×100 mL). The organic extractwas dried (MgSO₄), filtered and concentrated to give 2.0 g of a whitesolid, whose ¹H-NMR and MS were consistent with the desired title acid17.3-Benzyloxy-6-methoxypicolinic Acid (18).

A solution of methyl 3-benzyloxypicolinate (4.86 g) and3-chloroperoxybenzoic acid (5.75 g, 60% peracid) in CH₂Cl₂ (100 mL) wasstirred at room temperature for 40 hours. The reaction mixture was thenextracted with 5% sodium bisulfite solution (100 mL) then with 0.5N NaOHsolution (150 mL). After drying (MgSO₄) the solvent was evaporated togive 4.9 g of methyl 3-benzyloxypicolinate-1-oxide as a white solid.Recrystallization from methylcyclohexane/toluene gave a crystallinesolid, m.p. 104-106° C.

A solution of this compound (16.1 g) in acetic anhydride (80 mL) wasstirred and heated in an oil bath at 125° C. for 3 hours. The excessacetic anhydride was removed on a rotary evaporator and the residuetaken up in methanol (200 mL). Conc. sulfuric acid (1 mL) was added andthe resulting mixture heated at reflux for 90 minutes. The solvent wasevaporated then saturated sodium bicarbonate added to the residue. Theresulting mixture was extracted with CH₂Cl₂ (3×100 mL). The organicfractions were combined, dried (MgSO₄) and the solvent evaporated togive 15.5 g of methyl 3-benzyloxy-6-hydroxypicolinate as a yellow solid.Recrystallization from toluene gave a pale yellow solid, m.p. 91-92° C.

To a stirred solution of this compound (10.25 g) in toluene (125 mL),warmed in an oil bath at 60° C., was added silver carbonate (16.6 g),then methyl iodide (8.52 g). The resulting mixture was stirred andheated for 3 hours at 60° C. After cooling, the mixture was filteredthrough Celite® and the solvent evaporated to give a yellow oil. Silicagel chromatography (4:1 hexane/acetone) gave a nearly colorless oil,whose ¹H-NMR and MS data were consistent with methyl3-benzyloxy-6-methoxypicolinate. Hydrolysis of this ester to the titleacid 18 was accomplished with LiOH.H₂O as described above for relatedesters.4-Hydroxypyrimidine-5-carboxylic Acid (19).

Ethyl 4-hydroxypyrimidine-5-carboxylate can be prepared following theprocedure of M. Pesson et al., Eur. J. Med. Chem.—Chim. Ther. 1974, 9,585. A solution of this ester (500 mg, 3 mmol) in THF (10 mL) and MeOH(5mL) was treated with LiOH.H₂O (373 mg, 8.9 mmol) and stirredovernight. The mixture was quenched with conc. HCl (1 mL) and extractedwith EtOAc (2×20 mL). The combined organic extract was dried (MgSO₄) andconcentrated to give 260 mg of the title compound 19 as an orange solid,m.p. 220° C. (dec).4-Hydroxy-2-methylpyrimidine-5-carboxylic Acid (20).

Ethyl 4-hydroxy-2-methylpyrimidine-5-carboxylate was prepared followingthe procedure of Geissman et al., J. Org. Chem., 1946, 11, 741. Asolution of this ester (750 mg, 4.11 mmol) in THF (10 mL) and MeOH (5mL) was treated with LiOH.H₂O (431 mg, 10.3 mmol) and stirred overnight.The mixture was quenched with conc. HCl (1 mL) and extracted with EtOAc(2×20 mL). The combined organic extract was dried (MgSO₄) andconcentrated to give 155 mg of the title compound 20 as a white solid,m.p. 180° C. (dec).5,6-Dichloro-3-hydroxypyrazine-2-carboxylic Acid (21).

Methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (5.0 g, 23 mmol) wasstirred in conc. sulfuric acid (140 mL) and cooled to 0° C. Sodiumnitrite was added slowly, maintaining the temperature close to 0° C.After an additional 30 minutes at 0° C., the mixture was allowed to warmto ambient temperature and stirred for 3 hours. The mixture was pouredinto 500 g of ice, resulting in bubbling and foaming. After 30 minutes,the mixture was extracted 3 times with EtOAc. The combined organicextract was dried (MgSO₄), filtered and concentrated. The yellow solidwhich was left was washed with water and air-dried, to leave 5.0 g of ayellow solid, m.p. 114-116° C., whose ¹³C-NMR spectrum was consistentwith the methyl ester of the title compound.

This solid (5.0 g) was treated with 1N NaOH (20 mL) and the mixtureheated at 90° C. for 1.5 hours. After allowing to cool, the mixture wasacidified with conc. HCl, then extracted 3 times with EtOAc. Drying(MgSO₄), filtration and concentration afforded 0.48 g of a dark yellowsolid, whose ¹H-NMR and MS spectra were consistent with the title acid21.6-Chloro-3-hydroxy-5-methoxypyrazine-2-carboxylic Acid (22).

A stirred mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate(5.0 g, 23 mmol) and sodium methoxide (3.6 g, 67.5 mmol) in absoluteMeOH (50 mL) was heated at reflux for 2 hours, then allowed to cool andacidified with conc. HCl. The precipitate was collected by filtration,washed with water and air-dried to afford 3.6 g of a brown solid.Recrystallization from hexane-EtOAc (1:1) afforded 2.6 g of a paleyellow solid whose spectra were consistent with methyl3-amino-6-chloro-5-methoxypyrazine-2-carboxylate.

This compound (1 g, 4.6 mmol) was taken up in conc. sulfuric acid,cooled to 0° C., and treated slowly with sodium nitrite (0.5 g, 6.9mmol). After 30 minutes at 0° C., the mixture was poured into 300 g ofice/water, resulting in foaming. Stirring was continued for 30 minutes,then the solid was collected by filtration and washed with water. Thewet solid was taken up in EtOAc, dried (MgSO₄), filtered andconcentrated. This gave 0.95 g of an off-white solid, m.p. 180-182° C.,whose NMR spectra were consistent with methyl6-chloro-3-hydroxy-5-methoxypyrazine-2-carboxylate.

This solid (0.9 g, 4.1 mmol) was treated with 1N NaOH (60 mL), and themixture was stirred for 1 hour, then acidified with conc. HCl. Theprecipitate was collected by filtration and washed with water, then wasdissolved in EtOAc, dried (MgSO₄), filtered and concentrated. Thisafforded 0.62 g of a pale yellow solid, m.p. 170-173° C., whose spectrawere consistent with the desired title acid 22.

4-Hydroxyisothiazole-3-carboxylic Acid (23).

This acid was obtained following the procedure shown in Scheme 5.

Thus, to a stirred solution of solid KOH (88%, 6.98 g, 0.11 mol) in 75mL of EtOH in a flask flushed with nitrogen was added thiolacetic acid(8.36 g, 0.11 mol) washed in with 25 mL of EtOH. The mixture was stirredunder nitrogen for 5 minutes in the stoppered flask. To this was added0.1 mol of the crude bromo compound (freshly prepared according to M.Hatanaka and T. Ishimaru, J. Med. Chem., 1973, 16, 798). The flask wasflushed with nitrogen and stoppered. The mixture was stirred in anambient water bath for 3 hours, then was poured into 300 mL CH₂Cl₂ and1000 mL water. The aqueous layer was extracted four times with 200 mL ofCH₂Cl₂. The combined organic extracts were washed with 100 mL of coldwater and saturated salt solution and dried. The crude mixture wasfiltered and concentrated. The resulting oil was chromatographed onsilica gel, using diethyl ether as eluent, to give 13 g of a lightyellow oil which solidified on standing to a gummy solid. Spectral datawere consistent with ethyl 2-acetylamino-4-acetylthio-3-oxobutanoate.

To a rapidly stirred solution of this compound (12.95 g) in 450 mL ofchloroform, cooled in an ice bath to below 5° C., bromine (15.8 g, 2equivalents) in 50 mL of chloroform was added dropwise over 45 minutes.Stirring was continued in the ice bath for an additional 45 minutes, andthen at ambient temperature for 30 hours. Then the mixture was washedwith 200 mL of water, followed by another 100 mL of water. The combinedaqueous washes were re-extracted with 100 mL of chloroform. The combinedchloroform solutions were washed with saturated salt solution and driedover MgSO₄. The solution was filtered and concentrated to a crude oil.This was chromatographed on silica gel using a serial gradient frompetroleum ether-CH₂Cl₂ (3:1) to CH₂Cl₂, to give first 0.79 g of ethyl5-bromo-4-hydroxyisothiazole-3-carboxylate, and then 3.40 g of ethyl4-hydroxyisothiazole-3-carboxylate as colorless crystals, m.p. 44-7° C.,consistent by MS and ¹H-NMR.

To 710 mg of the latter ester in 30 mL of THF was added 370 mg ofLiOH.H₂O (2.2 equivalents) in 10 mL of water. The mixture was stirredfor 3 hours at ambient temperature, then cooled in the refrigerator. Theprecipitated solid was collected by filtration to give 710 mg of thedilithium salt of the carboxylic acid. This salt was taken up in 7 mL ofwater, cooled in an ice bath, and taken to pH 1 by addition of 2N HCl.The resulting solution was extracted three times with 50 mL of EtOAc.The combined extracts were washed with 5 mL of brine and dried (Na₂SO₄),filtered, and the filtrate placed in the refrigerator. The chilledsolution was re-filtered and the filtrate concentrated to give 230 mg ofa colorless solid, m.p. 185-89° C., whose ¹H-NMR and ¹³C-NMR spectrawere consistent with the title compound 23.3-Benzyloxy-1-methylpyrazole-4-carboxylic Acid (24) and5-Benzyloxy-1-methylpyrazole-4-carboxylic Acid (25).

A mixture of ethyl 3-hydroxy-1-methylpyrazole-4-carboxylate and ethyl5-hydroxy-1-methylpyrazole-4-carboxylate (obtained by the procedure ofY. Wang, et al., Zhejiang Gongxueyuan Xuebao, 1994, 2, 67), wasbenzylated according to the procedure of S. Yamamoto, et al., JapanesePatent JP 62148482, 1987, and the mixture was separated by columnchromatography, using 3:1 hexanes:EtOAc as the eluent, to provide ethyl3-benzyloxy-1-methylpyrazole-4-carboxylate and ethyl5-benzyloxy-1-methylpyrazole-4-carboxylate, which were pure by ¹H-NMR.

Ethyl 3-benzyloxy-1-methylpyrazole-4-carboxylate (283 mg, 1.08 mmol) inTHF (10 mL), MeOH (2 mL), and water (5 mL) was treated with LiOH.H₂O (91mg, 2.17 mmol) and stirred overnight. The mixture was quenched withconc. HCl (1 mL) and extracted with EtOAc (2×20 mL). The combinedorganic layers were dried (MgSO₄) and concentrated to give a white solid(227 mg), m.p. 169-172° C., whose spectra were consistent with3-benzyloxy-1-methylpyrazole-4-carboxylic acid (24).

Ethyl 5-benzyloxy-1-methylpyrazole-4-carboxylate (755 mg, 2.9 mmol) waslikewise hydrolyzed using LiOH.H₂O (243 mg, 5.8 mmol) in THF (20 mL),MeOH (4 mL), and water (10 mL), to afford 608 mg of5-benzyloxy-1-methyl-4-carboxylic acid (25) as a white solid, m.p.117-122° C.

Preparation of Other Heteroaromatic Carboxylic Acids.

4-Hydroxynicotinic acid was prepared by the procedure of M. Mittelbachet al., Arch. Pharm. (Weinheim, Germany) 1985, 318, 481-486.2-Hydroxy-6-methylnicotinic acid can be prepared following the method ofA. Dornow, Chem. Ber. 1940, 73, 153. 4,6-Dimethyl-2-hydroxynicotinicacid can be prepared following the method of R. Mariella and E. Belcher,J. Am. Chem. Soc., 1951, 73, 2616. 5-Chloro-2-hydroxy-6-methylnicotinicacid can be prepared by the procedure of A. Cale et. al., J. Med. Chem.,1989, 32, 2178. 2,5-Dihydroxynicotinic acid can be prepared by themethod of P. Nantka-Namirski and A Rykowski, Chem. Abstr., 1972, 77,114205. 3-Hydroxyisonicotinic acid was prepared according to the methodof J. D. Crum and C. H. Fuchsman, J. Heterocycl. Chem. 1966, 3, 252-256.3-Hydroxypyrazine-2-carboxylic acid can be prepared according to themethod of A. P. Krapcho et al., J. Heterocycl. Chem. 1997, 34, 27.5,6-Dimethyl-3-hydroxypyrazine-2-carboxylic acid can be prepared byhydrolysis of the corresponding ethyl ester, whose synthesis isdescribed by S. I. Zavyalov and A. G. Zavozin, Izv. Akad. Nauk SSSR,1980, (5), 1067-1070. 4-Hydroxypyridazine-3-carboxylic acid was preparedby the method of I. Ichimoto, K. Fujii, and C. Tatsumi, Agric. Biol.Chem. 1967, 31, 979. 3,5-Dihydroxy-1,2,4-triazine-6-carboxylic acid wasprepared by the method of E. Falco, E. Pappas, and G. Hitchings, J. Am.Chem. Soc., 1956, 78, 1938.5-Hydroxy-3-methylthio-1,2,4-triazine-6-carboxylic acid was preparedfollowing the method of R. Barlow and A. Welch, J. Am. Chem. Soc., 1956,78, 1258. Hydroxyisothiazole-, hydroxyisoxazole-, andhydroxypyrazole-carboxylic acids were prepared by the method of T. M.Willson et al., Bioorg. Med. Chem. Lett., 1996, 6, 1043.3-Hydroxy-1,2,5-thiadiazole-4-carboxylic acid was prepared by the methodof J. M. Ross et al., J. Am. Chem. Soc., 1964, 86, 2861.3-Hydroxyisoxazole-4-carboxylic acid was obtained following theprocedure described by K. Bowden et al., J. Chem. Soc. (C), 1968, 172.3-Hydroxy-1-phenylpyrazole-4-carboxylate was generated in accordancewith the method of A. W. Taylor and R. T. Cook, Tetrahedron, 1987, 43,607. 3-Benzyloxyquinoline-2-carboxylic acid was prepared following theprocedure of D. L. Boger and J. H. Chen, J. Org. Chem. 1995, 60,7369-7371.

General Preparation of the Intermidiate Amines and Anilines.

The synthesis of cyclic, acyclic and benzylamines was carried out by thereduction of the corresponding oximes either by use of metal hydrides ordissolving metal reactions as is illustrated by R. O. Hutchins and M. K.Hutchins in Comprehensive Organic Synthesis; B. M. Trost, Ed.; PergamonPress: Oxford, 1991; Vol 8, p. 65; or J. W. Huffman in ComprehensiveOrganic Synthesis; B. M. Trost, Ed.; Pergamon Press: Oxford, 1991; Vol8, p. 124. Alternatively, these amines could be prepared directly fromthe requisite ketones and aldehydes via a Leuckart reaction asexemplified by R. Carlson, T. Lejon, T. Lunstedt and E. LeClouerec, ActaChem. Scand. 1993, 47, 1046. The anilines in general were prepared bycatalytic reduction of the corresponding nitroaromatics using Pd oncharcoal or sulfided platinum on charcoal as catalysts. Such proceduresare well documented as in, for example, R. L. Augustine, CatalyticHydrogenation, Marcel Decker, Inc., New York, 1965.

The amines 49, which are 9-membered dilactone ring systems, wereprepared according to the procedures of M. Shimano, N. Kamei, T.Shibata, K. Inoguchi, N. Itoh, T. Ikari and H. Senda, Tetrahedron, 1998,54, 12745, or by modifications of these procedures. Such a modificationis shown in Scheme 6. Thus, 26 (from the above reference) was reducedwith lithium borohydride and the resulting primary alcohol capped withtriisopropylsilane (TIPS) to give 27. The free hydroxyl group of 27 wasreacted with 1-bromo-2-methyl-2-propene followed by catalytic reductionof the double bond to give 28. Selective removal of thepara-methoxybenzyl (PMB) blocking group followed by condensation withN-t-BOC-O-benzyl-L-serine gave 29. Removal of the TIPS group followed byoxidation of the resultant hydroxy group gave 30. This material (30) wassubsequently converted to the amine 31 using procedures described in theabove reference.

In a similar manner, the syntheses of aminodilactones 38 and 48, whichlack the exocyclic ester functionality, are outlined in Schemes 7 and 8,repectively.

Preparation of 27 (See Scheme 6).

To a solution of lithium borohydride (2.0M in THF, 7.5 mL, 15 mmol) in7.5 mL dry THF was added 0.1 mL trimethyl borate. This mixture wascooled under nitrogen atmosphere to −30° C. To this solution was addeddropwise a solution of compound 26 (4.58 g, 10 mmol) in 10 mL THF over a10 min period. The solution was stirred at −30° C. for 1 hr, then at 0°C. for 5 hrs. Saturated ammonium chloride solution (10 mL) was addeddropwise, the mixture was stirred for 10 min, and the phases wereseparated. The aqueous phase was extracted with EtOAc (2×25 mL), and thecombined organic phases were washed with saturated brine, dried oversodium sulfate, and evaporated to dryness. The crude product waschromatographed to give 2.1 g white solid. A sample recrystallized fromhexane-EtOAc gave fine white needles, m.p. 91-93° C. [α]_(D) ²⁵=+31.9°(C=1.04, CHCl₃). This diol (2.04 g, 6.22 mmol) was dissolved in 4 mL dryDMF and imidazole (680 mg, 10 mmol) was added. The solution was cooledin an ice-bath, and then triisopropylchlorosilane (1.39 mL, 6.5 mmol)was added over 2 min. The mixture was stirred at room temperature for 4hr, then poured into ice-water, and extracted with 20% ether in hexanes(3×15 mL). The combined organic phases were washed with brine, dried,and filtered through a short plug of silica gel, which was washed with20 mL of the same solvent. The solvent was evaporated to give 2.77 g ofcompound 27 as a pale viscous oil, which was very pure by ¹H-NMR.

Preparation of 28 (See Scheme 6).

Sodium hydride (60% oil dispersion, 400 mg, 10 mmol) was charged to a 50mL flask and washed three times with hexanes. DMF (15 mL) was added andthe suspension was stirred as compound 27 (2.53 g, 5.19 mmol) in 5 mLdry DMF was added dropwise over 15 min. The reaction was stirred for 15min and then cooled to below 10° C. and 1-bromo-2-methyl-2-propene (1mL, 10 mmol) was added over 5 min, followed by stirring for 2 hr at roomtemperature. The mixture was partitioned between hexanes/ice-coldammonium chloride solution, worked up as in preparation of 27, and thecrude product was chromatographed to give 2.20 g of colorless oil whichwas pure by ¹H-NMR and elemental analysis. This material (2.38 g, 4.4mmol) was dissolved in 50 mL of EtOAc in a 100 mL Morton flask undernitrogen. 150 mg of 5% Pt on carbon was added, and the mixture wasstirred under 1 atmosphere of hydrogen for 20 min. The catalyst wasremoved by filtration, and the solvent was evaporated to give 2.35 g of28 as a colorless oil which was pure by ¹H-NMR.

Preparation of 29 (See Scheme 6).

To a 50 mL flask equipped with magnetic stirring was charged a solutionof ether 28 (2.0 g, 3.68 mmol) in 40 mL CH₂Cl₂ and 2 mL water. This wasstirred under nitrogen and cooled in an ice-bath at <10° C. as2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (920 mg, 4.05 mmol) wasadded in one portion. The ice-bath was removed, and the mixture wasstirred for 1 hr. at room temperature. The gold suspension was suctionfiltered, the cake was washed with 2×10 mL CH₂Cl₂, and the filtrateswere extracted with 0.2N NaOH (2×25 mL). The organic layer was dried andconcentrated to give a pale oil, which was purified by chromatography togive 1.53 g of colorless oil which was pure by elemental analysis. Thiswas dissolved in 25 mL CH₂Cl₂ and stirred in an ice-bath under nitrogenas DMAP (854 mg, 7 mmol), EDCI (1.34 g, 7 mmol), andN-t-BOC-O-benzyl-L-serine (2.07 g, 7 mmol) were added sequentially. Thecooling bath was removed, and the mixture was stirred for 2 hr at roomtemperature. It was then poured into a rapidly stirring mixture of 50 mLof ice-cold 0.5N HCl and 20 mL of CH₂Cl₂ and stirred for 10 min. Thephases were separated and the aqueous phase was extracted with 1×10 mLCH₂Cl₂; then, the combined organic phases were dried and concentrated togive a pale oil. This was chromatographed to give 2.30 g of 29 as anearly colorless heavy oil. TLC and ¹H-NMR appeared quite pure.

Preparation of 30 (See Scheme 6).

Silyl ether 29 was dissolved in 7 mL dry pyridine and cooled in an icebath. HF-pyridine complex (4.5 mL) was added over a 1 min period and thesolution was stirred at room temperature for 17 hr, then heated to 50°C. for 4.5 hr, when conversion stopped. The mixture was poured intoice-water and extracted with 3×50 mL ether. The combined organic phaseswere washed with water, 1N HCl, then dried and concentrated to give anoil. This was chromatographed to give 1.23 g of desired alcohol as aviscous oil, as well as 365 mg of recovered 29. The alcohol (1.14 g,2.10 mmol) was dissolved in 10 mL DMF, and pyridinium dichromate (3.76g, 10 mmol) was added. After 21 hours, the mixture was poured intoice-water, 1N HCl was added until the pH was below three, and then solidsodium bisulfite was added until the orange color was discharged. Theaqueous phase was extracted with ether (3×50 mL). The organics werecombined, washed, dried (Na₂SO₄), and concentrated. The residue waschromatographed to give 811 mg of viscous oil which was pure enough tocarry on. The acid was dissolved in 30 mL of EtOAc and 200 mg ofPearlman's catalyst was added. The slurry was shaken under 50 psi ofhydrogen pressure for 4 hr, 300 mg fresh catalyst was added, and shakingwas continued for 2 hrs. It was then filtered and the solvent wasevaporated to give 30 as a viscous gum which was pure enough for furtheruse.

Threoninedithiane 33 (See Scheme 7).

Pentyldithiane 32 (Hirai, Heterocyles 1990, 30(2, Spec. Issue), 1101)(200 mg, 0.97 mmol) was dissolved in 10 mL of CH₂Cl₂ at roomtemperature. N-(Z)-O-t-Butyl-(L)-threonine (900 mg, 2.91 mmol) was addedfollowed by DMAP (36 mg, 0.29 mmol). To this mixture was added dropwisea solution of dicyclohexyl carbodiimide (DCC) (1M in CH₂Cl₂, 2.9 mL, 2.9mmol) followed by stirring at room temperature overnight. The reactionwas diluted with 50 mL of ether (Et₂O), filtered and concentrated. Theresulting residue was applied to a small (4″) silica gel gravity columnand eluted with 4:1 hexanes/EtOAc. The eluent collected from the silicagel column was further purified by radial chromatography using 4:1hexanes/EtOAc as the eluent. Product fractions were evaporated and keptunder high vacuum (45° C. @ 0.1 torr) to constant weight to give 500 mgof a nearly colorless heavy oil identified as dithiane 33 (TLCR_(f)=0.32, ¹H-NMR).

Threoninecarboxylic Acid 35 (See Scheme 7).

Threoninedithiane 33 (500 mg, 1.01 mmol) was dissolved in 10 mL of a 9:1CH₃CN/H₂O mixture at room temperature.[Bis(trifluoroacetoxy)iodo]benzene (650 mg, 1.50 mmol) was added and thereaction was stirred for 10 min. Saturated NaHCO₃ was added (20 mL) andthe solution was extracted with Et₂O (3×20 mL). The ethereal layer wasdried over MgSO₄, filtered, and concentrated. The aldehyde 34 wassufficiently pure (TLC, GC/MS) for use directly in the next reaction.The crude aldehyde was taken up in 15 mL (4.95 mmol) of CrO₃ reagent(made from 1 g CrO₃, 30 mL of CH₃CO₂H and 1 mL pyridine) and stirred atroom temperature overnight. The solution was diluted with 30 mL coldwater and extracted with Et₂O (3×30 mL). The organic layer was washedwith 30 mL brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified via radial chromatography using 2:1 heptane/EtOAccontaining 2% CH₃CO₂H as the eluent. The carboxylic acid 35 (120 mg) wasquite pure by TLC and ¹H-NMR.

Threoninehydroxycarboxylic Acid 36 (See Scheme 7).

Threoninecarboxylic acid 35 (137 mg, 0.324 mmol) was stirred in 3 mL oftrifluoroacetic acid for 10 min and the mixture was concentrated on arotary evaporator. The residue was dried under high vacuum (0.05 mm)overnight. The hydroxyacid 36 (119 mg) was used directly in the nextstep.

N-Cbz-Threoninebislactone 37 (See Scheme 7).

Threoninehydroxycarboxylic acid 36 (119 mg, 0.324 mmol) was dissolved in1 mL benzene and Aldrithiol™-2 was added (85 mg, 0.39 mmol) followed bytriphenylphosphine (0.39 mmole, 101 mg) and the reaction was stirredovernight. The crude thioester was diluted with 15 mL of CH₃CN. Aseparate flask equipped with a reflux condenser was charged with 1.2 mL(1.16 mmol) of a 1.0 M AgClO₄ solution in toluene, followed by 32 mL ofCH₃CN. This solution was heated to a reflux rate of 5-10 drops persecond (oil bath ˜160° C.). The thioester solution was then addeddropwise via an addition funnel at the top of the condenser over 2 hr.The mixture was refluxed an additional 30 min, cooled and concentrated.The residue was diluted with 10 mL 0.5 M KCN and extracted with benzene(3×20 mL). The benzene layers were combined, washed with 20 mL water,dried over MgSO₄, filtered and concentrated. The residue was then takenup in 10 mL 2:1 pentane/Et₂O and filtered. The solids were washed with2:1 pentane/Et₂O and the combined organic solution was concentrated.Radial chromatography (2:1 pentane/Et₂O as the eluent) provided 34 mg ofthe bislactone 37, quite pure by TLC (R_(f)=0.22) and ¹H-NMR.

3-Amino-4,7,9-trimethylbislactone (38) (See Scheme 7).

N-Cbz-Threoninebislactone 37 (34 mg, 0.097 mmol) was dissolved in 10 mLof methanol in a 500 mL Parr bottle and purged with nitrogen. To thissolution was added 10 mg of Pd (black) and the mixture was shaken at 45psi hydrogen pressure for 1 hr. The catalyst was filtered and thesolvent was evaporated to give the free amine 38 (20 mg, 100%). Thisamine was pure enough (¹H-NMR), and was used as such without furtherpurification.

3-Benzyl-4-hydroxy-5-methylbutyrolactone (40) (See Scheme 8).

Pentanoic acid 39 (Shimano et al., Tetrahedron Lett. 1998, 39, 4363)(1.8 g, 5.23 mmol) was dissolved in 30 mL of methanol in a 500 mL Parrbottle and purged with nitrogen. To this solution was added 150 mg of10% Pd on carbon followed by 6 drops of conc. HCl. The mixture wasshaken at 50 psi hydrogen pressure for 3 hr. The catalyst was filteredthrough diatomaceous earth and the solution concentrated. The residuewas taken up in 30 mL CH₂Cl₂ and washed with water (1×10 mL). Thesolution was dried over MgSO₄, filtered, and concentrated. Crude ¹H-NMRand GC/MS revealed expected butyrolactone 40 and 4-methylanisole in a4:1 ratio (v/v). This material (60% purity by GC) was used directly inthe next reaction.

3-Benzyl-5-methylbutenolide 41 (See Scheme 8).

3-Benzyl-4-hydroxy-5-methylbutyrolactone 40, (60% purity, 1.7 g, 8.25mmol), was dissolved in 25 mL CH₂Cl₂ and cooled to 0° C. The solutionwas stirred while triethylamine (2.3 mL, 16.5 mmol), DMAP (500 mg, 4.13mmol) and p-toluenesulfonyl chloride (9.0 mmol, 1.7 g) were addedsequentially. The reaction was warmed to room temperature and stirred 30hr. The reaction was diluted with 50 mL Et₂O and washed with 5% NaHCO₃(25 mL). The solution was dried over MgSO₄, filtered and concentrated.The residue was purified via radial chromatography using 2:1pentane/Et₂O as the eluent to yield 677 mg of the butenolide 41 (>95%purity by GC and ¹H-NMR).

cis-3-Benzyl-5-methylbutyrolactone 42 (See Scheme 8).

3-Benzyl-5-methylbutenolide 41 (677 mg, 3.60 mmol) was dissolved in 30mL of EtOAc in a 500 mL Parr bottle and purged with nitrogen. To thissolution was added 300 mg of 10% Pd/C and the mixture was shaken at 45psi hydrogen pressure overnight. The catalyst was filtered and thesolvent was evaporated. The residue was purified via radialchromatography using 2:1 pentane/Et₂O as the eluent to give 484 mg of acolorless oil (71% yield of material pure by ¹H-NMR in CDCl₃ and by GC).

2-Benzylpentyldithiane 43 (See Scheme 8).

cis-3-Benzyl-5-methylbutyrolactone 42 (550 mg, 2.89 mmol) was dissolvedin 15 mL of Et₂O and cooled to −78° C. Diisobutylalmuminum hydride (1.0M in hexanes, 3.47 mmol, 3.5 mL) was added dropwise and the solution wasstirred at −78° C. for 2 hrs. Methanol (3.3 mL) was added over 15 minand the reaction was stirred at −78° C. for an additional 30 min. Sodiumpotassium tartrate (1.65 g in 5 mL of water) was added and the reactionwas allowed to warm to room temperature and stirred overnight. Thelayers were separated and the aqueous layer was extracted with Et₂O(2×10 mL). The combined ethereal layers were washed with satd. NaHCO₃and brine (1×10 mL). The solution was dried over MgSO₄, filtered, andconcentrated. The crude lactol (555 mg) was dissolved in 5 mL of CH₂Cl₂and cooled to 0° C. 1,3-Propanedithiol (3.46 mmol, 0.35 mL) was addedfollowed by 0.37 mL (2.89 mmol) of boron trifluoride etherate. Thereaction was allowed to warm to room temperature and stirred overnight.Saturated NaHCO₃ was added (20 mL) and the mixture stirred 1 hr. Thelayers were separated and the aqueous layer extracted with CH₂Cl₂ (2×10mL). The combined organic layers were washed with brine (1×20 mL), driedover MgSO₄, filtered, and concentrated. The residue was purified viaradial chromatography using 3:1 hexane/EtOAc as the eluent to give 560mg of a yellow oil (69% yield of material pure by ¹H-NMR and GC)identified as dithiane 43.

Serinedithiane 44 (See Scheme 8).

2-Benzylpentyldithiane 43 (560 mg, 1.99 mmol) was dissolved in 5 mL ofDMF and cooled to 0° C. DMAP (0.29 mmol, 36 mg) was added followed byEDCI, (0.57 g, 2.98 mmol). N-t-BOC-O-benzyl-(L)-serine (760 mg, 2.58mmol) was then added followed by warming to room temperature andstirring at room temperature overnight. The reaction was poured into arapidly stirring mixture of 10 mL ice cold 0.5 N HCl and 20 mL 20%ether/hexanes and stirred 10 min. The layers were separated and theaqueous layer extracted with 20% ether/hexanes (1×10 mL). The combinedorganic layers were washed with 0.5 N HCl (20 mL) and brine (2×20 mL).The solution was dried over MgSO₄, filtered, and concentrated. Theresulting residue was kept under high vacuum (45° C. @ 0.1 torr) toconstant weight to give 1.06 g of a nearly colorless heavy oilidentified as dithiane 44 (TLC R_(f)=0.3, 3:1 hexanes/EtOAc).

N-t-BOC-O-benzylserinecarboxylic Acid 45 (See Scheme 8).

Serinedithiane 44 (1.06 g, 1.90 mmol) was dissolved in 20 mL of a 9:1CH₃CN/H₂O mixture at room temperature.[Bis(trifluoroacetoxy)iodo]benzene (1.2 g, 2.82 mmol) was added and thereaction stirred for 10 minutes. Saturated NaHCO₃ was added (40 mL) andthe solution extracted with Et₂O (3×40 mL). The ethereal layer was driedover MgSO₄, filtered and concentrated. The aldehyde was sufficientlypure (TLC, GC/MS, ¹H-NMR) for use directly in the next reaction. Thecrude aldehyde was taken up in 30 mL (9.70 mmol) of CrO₃ reagent (madefrom 1 g CrO₃, 30 mL of CH₃CO₂H and 1 mL pyridine) and stirred at roomtemperature overnight. The solution was diluted with 60 mL cold waterand extracted with Et₂O (3×60 mL). The organic layer was washed with2×60 mL brine, dried over MgSO₄, filtered and concentrated. The residuewas taken up in 100 mL 2:1 heptane/EtOAc and evaporated. The residue waspurified via radial chromatography using 1.5:1 heptane/EtOAc containing2% CH₃CO₂H as the eluent. The carboxylic acid (536 mg) looked quite pureby TLC and ¹H-NMR with two t-BOC rotamers evident in CDCl₃ but not inacetone-d₆.

N-t-BOC-serinebislactone 47 (See Scheme 8).

N-t-BOC-O-Benzylserinecarboxylic acid 45 (536 mg, 1.11 mmol) wasdissolved in 15 mL of EtOAc in a 500 mL Parr bottle and purged withnitrogen. To this solution was added 390 mg of 10% Pd/C and the mixturewas shaken at 50 psi hydrogen pressure for 17 hr. The catalyst wasfiltered through diatomaceous earth and the solvent was evaporated togive the hydroxyacid 46 (440 mg). The crude hydroxyacid 46 was dissolvedin 23 mL benzene and triphenylphosphine (0.34 g, 1.28 mmol) was added atroom temperature. Diisopropylazodicarboxylate (DIAD, 0.25 mL, 1.28 mmol)was added dropwise and the reaction was stirred at room temperatureovernight. The solution was concentrated and the resulting residue wasapplied to a small (4 in) gravity column and eluted with 2:1hexanes/EtOAc. The eluent from the silica gel column was furtherpurified by radial chromatography using 2:1 pentane/ether as the eluent.Product fractions were evaporated to give 132 mg of a yellow oilidentified as N-t-BOC-serinebislactone 47 (TLC R_(f)=0.32, quite pure by¹H-NMR).

3-Amino-7-benzyl-9-methylbislactone 48 (See Scheme 8).

N-t-BOC-Serinebislactone 47 (132 mg, 0.35 mmole) was stirred in 3 mL oftrifluoroacetic acid for 30 minutes and the reaction was concentrated ona rotary evaporator. The residue was dried under high vacuum (0.05 mm)overnight. The trifluoroacetic acid salt of amine 48 (0.35 mmol) wasquite pure by ¹H-NMR, and was used as such without further purification.3-(3-Chlorophenoxy)aniline.

To a stirred solution of potassium t-butoxide (12.3 g) in DMSO (100 mL)was added at once 3-chlorophenol (12.86 g). The resulting solution wasstirred for 5 minutes at room temperature, then 3-fluoronitrobenzene(12.70 g) was added all at once. The resulting dark mixture was heatedat 120° C. for 12 hours, cooled to room temperature then poured intowater (700 mL). The resulting mixture was extracted with ether (2×200mL). The organic fraction was washed with 2N NaOH (100 mL), then withwater (100 mL). After drying (MgSO₄), the solvent was evaporated and theresulting dark oil was distilled to give 3-(3-chlorophenoxy)nitrobenzeneas a yellow oil, b.p. 135-140° C. at 0.05 mm.

A mixture of 3-(3-chlorophenoxy)nitrobenzene (14 g), and 5% Pt onsulfided carbon (1.25 g) in EtOAc (150 mL) was subjected to a hydrogenatmosphere (initial pressure=50 psi) on a Parr shaker. After 4 hours,the mixture was thoroughly degassed (hydrogen replaced with nitrogen),dried (MgSO₄), and filtered (#50 Whatman paper). The solvent wasevaporated to give a pale yellow oil (12 g) which was >96% pure by GC.¹H-NMR (CDCl₃) and GC/MS (m/e=219, 221) were consistent with3-(3-chlorophenoxy)aniline.3-(4-Trifluoromethylphenoxy)aniline.

To a stirred solution of 3-hydroxyaniline (6.55 g) and4-fluorobenzotrifluoride (9.85 g) in DMSO (50 mL) was added in oneportion potassium tert-butoxide (7.86 g). The resulting dark solutionwas heated for 4 hours at 95° C., cooled to room temperature, thenpoured into water (600 mL). The mixture was extracted with ether (3×125mL). The organic phase was washed with 2N sodium hydroxide (2×75 mL) andwater (100 mL), dried (MgSO₄) and the solvent evaporated to give a darkoil. This oil was distilled to give the title aniline as a colorless oil(8.7 g), b.p. 110-112° C. at 0.15 mm.4-(4-Trifluoromethylphenylthio)aniline.

To a stirred solution of 4-fluorobenzotrifluoride (9.85 g) and4-aminothiophenol (7.51 g) in DMSO (60 mL), cooled in an ice bath, wasadded in one portion potassium t-butoxide (6.73 g). The resultingmixture was stirred at 0° C. for 10 minutes, then at 60° C. overnight.After cooling, the mixture was poured into water (600 mL) and theresulting mixture extracted with ether (2×200 mL). The organic phase waswashed with 2N sodium hydroxide (50 mL), then with water (50 mL). Afterdrying (MgSO₄), the solvent was evaporated to give a brown solid.Recrystallization from hexane gave the title aniline as a yellow solid,m.p. 97-99° C.4-(3-Trifluoromethylbenzyl)aniline.

A Grignard reagent was prepared by adding a solution of4-bromo-N,N-bis-(trimethylsilyl)aniline (9.48 g) in dry THF (75 mL) to astirred mixture of magnesium turnings (1.09 g) in dry THF (10 mL). Asecond solution of the catalyst, Li₂CuCl₄ (0.33 g), was prepared byadding CuCl₂ (0.20 g) and LiCl (0.13 g) to dry THF (25 mL) and stirringuntil a homogeneous solution resulted. This catalyst solution was thenadded to a solution of 3-thrifluormethylbenzyl bromide (7.17 g) in dryTHF (75 mL). The orange-red solution was cooled in an ice bath (N₂atmosphere) and the above Grignard solution (previously cooled in an icebath) was rapidly transferred via cannula into it. After stirring for 15minutes at 0° C., the mixture was stirred overnight at room temperature.The reaction mixture was quenched by the addition of saturated NH₄Clsolution (25 mL). The organic phase was separated, dried (MgSO₄) and thesolvent evaporated to give a dark oil (11 g). To this oil was added 4 NHCl (50 mL), and the resulting mixture stirred at room temperature for 3hours. The mixture was made basic by the careful addition of solidsodium carbonate, then extracted with ether (3×100 mL). The organicphase was dried (MgSO₄) and the solvent evaporated. EtOAc (100 mL) wasadded and the solution decanted from some insoluble material. Again thesolvent was evaporated and the residue chromatographed (silica gel, 3:1hexane/EtOAc). The second eluate was collected to give an orange oil,which darkened rapidly. The NMR (CDCl₃) and GC/MS (m/e=251) wereconsistent with the title compound. This material was converted to theHCl salt to give a brown solid.4-(3-Trifluoromethylbenzoyl)aniline.

A stirred solution of 4-bromo-N,N-bis-(trimethylsilyl)aniline (9.24 g)in dry THF (100 mL) was cooled to −78° C. under an argon atmosphere. Tothis was slowly added a 2.5 M solution of n-butyllithium in hexane (12mL). After the addition was complete, the reaction mixture was stirredat −78° C. for 10 minutes, then a solution ofN-methyl-N-methoxy-3-trifluoromethylbenzamide (6.8 g) in dry THF (25 mL)was added dropwise. After the addition was complete, the mixture wasstirred at −78° C. for 1 hour, then the cooling bath removed and thereaction temperature allowed to warm to 10° C. The reaction was quenchedby the addition of saturated NH₄Cl solution (50 mL), then water (10 mL).The organic phase was separated, dried (MgSO₄) and the solventevaporated to give a yellow liquid (12 g). This was taken up in ether(100 mL), and 4N HCl (100 mL) added. The resulting mixture was stirredfor 30 minutes at room temperature, during which time a solid separated.This solid was filtered, washed with several portions of ether, thencarefully added to a stirred, saturated NaHCO₃ solution (100 mL). Theresulting mixture was extracted with ether (2×100 mL), the organic phasedried (MgSO₄), and the solvent evaporated to give a yellow-white solid(5.7 g). Recrystallization from methanol/water gave a white solid, m.p.130-131° C. Spectral data were consistent with the title compound.Ethyl 2-Amino-5-(4-trifluoromethylphenoxy)benzoate.

To a mechanically stirred solution of potassium t-butoxide (15.71 g) inDMSO (75 mL) was added in one portion 5-hydroxyanthranilic acid (10.2g). The mixture was stirred at room temperature under an argonatmosphere for 10 minutes, then 4-fluorobenzotrifluoride (11.16 g) wasadded, and the resulting mixture stirred and heated at 75-80° C.overnight. After cooling, the mixture was poured into water (600 mL) andthe pH adjusted to approximately 2.5. The resulting solid was filtered,washed with several portions of water, then recrystallized frommethanol/water (charcoal) to give a tan solid (13.5 g), m.p. 165-167° C.This solid was taken up in anhydrous ethanol (250 mL) and conc. sulfuricacid (15 mL) was carefully added. The resulting mixture was heated atreflux for 24 hours, then most of the ethanol evaporated. The residuewas carefully added to ice water (600 mL), the resulting mixture madebasic by the slow addition of 50% NaOH solution, and then extracted withether (2×150 mL). The organic phase was washed with water (100 mL) thensaturated NaCl solution (50 mL). After drying (MgSO₄), the solvent wasevaporated to give a yellow oil of about 98% GC purity. GC/MS indicateda parent of ion m/e=325, consistent with the title compound.2-Aminobenzonorbornane.

To a stirred solution of benzonorbornene (2.84 g) in dry THF (8 mL)cooled to 0° C. under an argon atmosphere was added rapidly a 1Msolution of borane in THF (6.7 mL). The solution was stirred for 10minutes at 0° C. then at room temperature for 90 minutes. The reactionmixture was again cooled to 0° C. and hydroxylamine-O-sulfonic acid(1.58 g) was added in one portion. The ice bath was removed and thereaction mixture was stirred at room temperature for 2 hours. 1N HCl (25mL) and ether (20 mL) were added and stirring continued for 10 minutes.The phases were separated and the organic phase discarded. The aqueousphase was made basic by the careful addition of 50% NaOH solution, thenextracted with ether (3×30 mL). The organic phase was dried (MgSO₄) andthe solvent evaporated to give a yellow liquid (1.35 g) which was 98%pure as judged from GC. The NMR (CDCl₃) and GC/MS (m/e=159) wereconsistent with the title compound.

Preparation of Mixture of(3-Trifluoromethylbenzyloxymethyl)norbonylamines 53.

Preparation of this mixture is depicted in Scheme 9. Thus, a mixture ofexo- and endo-norbornenecarboxylic acids 49 (˜1:4 ratio) (7.0 g),2-iodopropane (12.8 g) and potassium carbonate (10.4 g) in DMSO (40 mL)was stirred and heated at 55° C. overnight. After cooling the mixturewas diluted with water (125 mL), then extracted with pentane. Theorganic phase was dried (MgSO₄) and the solvent evaporated to give acolorless oil (8.2 g). This oil was added to a solution of sodium2-propoxide (3.6 g) in 2-propanol (100 mL) and the resulting mixtureheated at reflux for 16 hours. Removal of the 2-propanol, dilution withwater (200 mL), and pentane extraction gave the norbornene isopropylester 50 as a 52:48 exo to endo mixture. This was separated into pureisomers via chromatography (silica gel, 95:5 hexane/EtOAc). The exoisomer of 50 (4.0 g) was dissolved in ether (50 mL), cooled to 0° C.,and a 1M solution of lithium aluminum hydride in ether (14 mL) wasslowly added. After the addition was complete, the mixture was heated atreflux for 1 hour. After cooling, the reaction was quenched by thesequential addition of water (0.53 mL), 15% NaOH solution (0.53 mL),then water (1.59 mL). The resulting mixture was dried (MgSO₄), filtered,and the solvent evaporated to give the exo-alcohol 51 (2.7 g) as acolorless liquid. The GC/MS (m/e=124) was consistent with the assignedstructure.

To a stirred mixture of potassium hydride (1.0 g) in dry THF (25 mL) wascarefully added a solution of 51 (2.7 g) in THF (10 mL). After theaddition was complete, the mixture was stirred at room temperature for30 minutes, then 3-trifluoromethylbenzylbromide (5.98 g) was added allat once (exothermic reaction). The reaction was heated at reflux for 2hours, cooled, then poured into water (150 mL). Ether extraction (2×75mL), drying (MgSO₄) and solvent evaporation gave a yellow oil, which waspurified via chromatography (silica gel, 97:3 hexane/acetone) to givepure 52 as a colorless oil (5.2 g). NMR (CDCl₃) and GC/MS (m/e=282) wereconsistent with the structure of 52.

Conversion of 52 to the diastereomeric mixture of amines 53 wasaccomplished via the borane/hydroxylamine-O-sulfonic acid proceduredescribed earlier (20% yield).3-(3-Pyridyl)-1-propanamine.

This amine was obtained by initially converting 3-(3-pyridyl)-1-propanolto the corresponding chloride following the procedure of B. Jursic etal., Synthesis, 1988, (11), 868, then transforming this chloride to theamine via the procedure of D. J. Dumas et al., J. Org. Chem., 1988, 53,4650.3-[[5-(Trifluoromethyl)-2-pyridyl]oxy]-1-propanamine.

2-Fluoro-5-trifluoromethylpyridine (1.831 g, 11 mmol) was dissolved inanhydrous THF (15 mL) with stirring under nitrogen and cooled to 0° C.in an ice bath. To this was added dropwise over 30 minutes a solution of3-amino-1-propanol (0.76 mL, 10 mmol) in anhydrous THF (15 mL) and 1Mpotassium tert-butoxide in THF (10 mL, 10 mmol). The yellow solution wasallowed to stir and warm to room temperature in the ice bath overnight.The reaction mixture was poured into water (75 mL) and extracted withether (2×50 mL). The organic phase was washed with brine (50 mL), dried(Na₂SO₄), filtered and evaporated under vacuum to a yellow liquid, whichwas nearly pure by NMR and MS, and was used as such without furtherpurification.(+)-Trans-1-Hydroxy-2-aminocyclopentane Hydrobromide.

(±)-trans-1-Benzyloxy-2-aminocyclopentane hydrobromide (8.2 g, 42.8mmol) was treated with 40% HBr (60 mL). After stirring for 3 days, thesolution was concentrated in vacuo to provide 7.09 g (91%) of thehydrobromide salt as an orange solid which was pure by ¹H-NMR (DMSO-d₆).2,3-Dihydro-2,2-dimethyl-1H-inden-1-amine.

This amine was prepared according to the procedure of world patent WO9927783.

10-Amino-endo-2,5-methanobicyclo[4.4.0]dec-3-ene (56).

This compound was prepared as shown in Scheme 10. Thus, aluminumchloride (700 mg, 5.2 mmol) was added to a solution of2-cyclohexen-1-one (2.0 g, 20.8 mmol) in toluene (200 mL). After 40 min,freshly distilled cyclopentadiene (13.7 g, 208 mmol) was added andheated to 100° C. for 2 hours. After cooling, the mixture was dilutedwith Et₂O (300 mL) and washed with satd. NaHCO₃ (2×150 mL) and brine(100 mL). The combined organic layers were dried (MgSO₄), filtered andconcentrated. The residue was purified via flash chromatography using50:1 hexanes:Et₂O as the eluent, to provide the endo (1.74 g) and exo(943 mg) isomers of 2,5-methanobicyclo[4.4.0]dec-3-en-10-one (54), whichwere pure by ¹H-NMR and GC/MS.

Sodium acetate (1.79 g, 21.8 mmol) was added portionwise to a solutionof endo-2,5-methanobicyclo[4.4.1]dec-3-en-10-one (54) (1.61 g, 9.9 mmol)and hydroxylamine hydrochloride (758 mg, 10.9 mmol) in methanol (33 mL),and stirred overnight at room temperature. The reaction was quenchedwith H₂O and extracted with ether (2×50 mL). The combined organic layerswere dried (MgSO₄), filtered and concentrated to provideendo-2,5-methanobicyclo[4.4.0]dec-3-en-10-one oxime (55) as a pastyresidue, pure by ¹H-NMR and GC/MS.

endo-2,5-Methanobicyclo[4.4.1]dec-3-en-10-one oxime (55) (500 mg, 2.79mmol) was dissolved in EtOAc (25 mL) and 10% Pd/C (50 mg) was added.After 3 hours under H₂ (40 psi), the suspension was filtered throughCelite® and concentrated. The resulting residue was dissolved in EtOH(25 mL) and charged with Raney®-Ni (1.0g). The suspension was saturatedwith NH₃ and pressurized with H₂ (45 psi). After 6 hours the suspensionwas filtered through Celite®, diluted with EtOAc (100 mL), and washedwith satd. NaHCO₃ (100 mL). The combined organic layers were dried overMgSO₄, filtered and concentrated. ¹H-NMR and GC/MS revealed the titleamine 56 as a 2:1 mixture of diastereomers (418 mg).

10-Amino-4-(4′-methylpent-3′-enyl)-bicyclo[4.4.0]dec-3-ene (59).

Preparation of this compound was accomplished as shown in Scheme 11.Thus, aluminum chloride (700 mg, 5.2 mmol) was added to a solution of2-cyclohexen-1-one (2.0 g, 20.8 mmol) in toluene (100 mL). After 40 min,myrcene (17 g, 125 mmol) was added and heated to 100° C. for 2 hours.After cooling, the mixture was diluted with Et₂O (300 mL) and washedwith satd. NaHCO₃ (2×150 mL) and brine (100 mL). The combined organiclayers were dried over MgSO₄, filtered and concentrated. The residue waspurified via flash chromatography using 50:1 hexanes:Et₂O as the eluentto provide 4-(4′-methylpent-3′-enyl)-bicyclo[4.4.0]dec-3-en-10-one (57)(2.55 g), which was pure by ¹H-NMR and GC/MS.

Sodium acetate (1.73 g, 21 mmol) was added portionwise to a solution of4-(4′-methylpent-3′-enyl)-bicyclo[4.4.0]dec-3-en-10-one (57) (2.23 g,9.6 mmol) and hydroxylamine hydrochloride (733 mg, 10.5 mmol) inmethanol (32 mL), and stirred overnight at room temperature. Thereaction was quenched with H₂O and extracted with ether (2×50 mL). Thecombined organic layers were dried over MgSO₄, filtered andconcentrated. This gave4-(4′-methylpent-3′-enyl)-bicyclo[4.4.0]dec-3-en-10-one oxime (58) as apasty residue, pure by ¹H-NMR and GC/MS.

4-(4′-Methylpent-3′-enyl)-bicyclo[4.4.0]dec-3-en-10-one oxime (600 mg,2.42 mmol) was dissolved in EtOH (25 mL) and charged with Raney®-Ni (1.0g). The suspension was saturated with NH₃ and pressurized with H₂ (45psi). After 6 hours, the suspension was filtered through Celite®,diluted with EtOAc (100 mL), and washed with satd. NaHCO₃ (100 mL). Thecombined organic layers were dried over MgSO₄, filtered andconcentrated. ¹H-NMR and GC/MS were indicative of the pure title amine(550 mg).

2-Amino-7-furyl-3-methyl-4-chromanone Hydrochloride (63).

This amine hydrochloride salt was prepared as shown in Scheme 12. Thus,7-trifluoromethanesulfonate-3-methyl-4-chromanone (3.0 g, 9.7 mmol)(prepared according to the procedure of K. Koch, and M. S. Biggers, J.Org. Chem. 1994, 59, 1216) was added to a solution of2-(tributylstannyl)furan (3.79 g, 10.6 mmol), Pd(PPh₃)₄ (223 mg, 0.19mmol), LiCl (1.23 g, 29.0 mmol), and two crystals of2,6-di-t-butyl-4-methylphenol in 1,4-dioxane (50 mL), and heated toreflux for 12 hours. After cooling, the mixture was quenched with satd.NH₄Cl (40 mL) and extracted with Et₂O (2×50 mL). The combined organiclayers were dried over MgSO₄, filtered and concentrated. The residue waspurified via flash chromatography using 20:1 hexanes:EtOAc as the eluentto provide 7-furyl-3-methyl-4-chromanone (60) (1.78 g) as a yellowsolid, m.p. 94-95° C.

Sodium acetate (395 mg, 4.82 mmol) was added portionwise to a solutionof 7-furyl-3-methyl-4-chromanone (60) (500 mg, 2.19 mmol) andhydroxylamine hydrochloride (167 mg, 2.41 mmol) in methanol (5 mL), andstirred overnight at room temperature. The reaction was quenched withH₂O and extracted with ether (2×25 mL). The combined organic layers weredried over MgSO₄, filtered and concentrated to give7-furyl-3-methyl-4-chromanone oxime (61) as a white solid, m.p. 175-177°C.

Toluenesulfonyl chloride (397 mg, 2.08 mmol) was added to a 0° C.solution of 7-furyl-3-methyl-4-chromanone oxime (61) (461 mg, 1.89 mmol)and pyridine (0.5 mL) in CH₂Cl₂ (10 mL). After 6 hours, the mixture wasdiluted with CH₂Cl₂ (30 mL) and washed with 5% HCl (20 mL). The organiclayer was dried over MgSO₄, filtered and concentrated. The residue waspurified via flash chromatography using 5:1 hexanes:EtOAc as the eluent,to provide 7-furyl-3-methyl-4-chromanone O-(toluenesulfonyl)-oxime (62)(429 mg) as a pink solid, m.p. 163-164° C. (dec).

An ethanolic solution of sodium ethoxide (0.35 mL, 2.87 M, 1.0 mmol) wasadded to a stirred solution of7-furyl-3-methyl-4-chromanone-O-(toluenesulfonyl)-oxime (62) (410 mg,1.0 mmol) in benzene (4 mL). After 18 hours, 3N HCl (6 mL) was added andthe layers were separated. The organic phase was further extracted with3N HCl (2×10 mL), and the combined aqueous extracts were concentrated toprovide the crude title compound 63 as an orange solid (388 mg), whichwas used as is without further purification.

2-Amino-7-(3′-methoxypropynyl)-3-methyl-4-chromanone Hydrochloride (65).

This amine hydrochloride was prepared as shown in Scheme 13. Thus,7-trifluoromethanesulfonate-3-methyl-4-chromanone (3.10 g, 10 mmol)(prepared according to the procedure of K. Koch and M. S. Biggers, J.Org. Chem. 1994, 59, 1216) was added to a solution of methyl propargylether (1.05 g, 15 mmol), (Ph₃P)₄Pd (210 mg, 0.30 mmol), and Et₃N (6 mL)in DMF (30 mL) and heated at 70° C. for 1 hour. After cooling, themixture was quenched with satd. NH₄Cl (40 mL) and extracted with Et₂O(2×50 mL). The combined organic layers were dried over MgSO₄, filteredand concentrated. The residue was purified via flash chromatographyusing 9:1 hexanes-EtOAc as the eluent to provide7-(3′-methoxypropynyl)-3-methyl-4-chromanone (64) (1.40 g) as a whitesolid, m.p. 60-63° C.

Conversion of 64 to the title compound 65 was accomplished in the samemanner as described above for 2-amino-7-furyl-3-methyl-4-chromanonehydrochloride.

2-Amino-α-tetralone Hydrochloride (66).

This compound was obtained from α-tetralone as shown in Scheme 14, bythe same procedure described above for2-amino-7-furyl-3-methyl-4-chromanone hydrochloride.

2-Amino-endo-6,9-ethanobicyclo[4.4.0]dec-7-enone Hydrochloride (70).

This amine hydrochloride was prepared as shown in Scheme 15. Thus,aluminum chloride (700 mg, 5.2 mmol) was added to a solution of2-cyclohexen-1-one (2.0 g, 20.8 mmol) in toluene (100 mL). After 40 min,cyclohexadiene (8.3 g, 104 mmol) was added and heated to 100° C. for 2hours. Upon cooling, the mixture was diluted with Et₂O (300 mL) andwashed with satd. NaHCO₃ (2×150 mL) and brine (100 mL). The combinedorganic layers were dried over MgSO₄, filtered and concentrated. Theresidue was purified via flash chromatography using 50:1 hexanes-Et₂O asthe eluent to provide endo-2,5-ethanobicyclo[4.4.0]dec-7-en-10-one (67)(2.77 g), which was pure by ¹H-NMR and GC/MS.

A solution of endo-2,5-ethanobicyclo[4.4.0]dec-7-en-10-one (67) (2.17 g,12.3 mmol) in THF (20 mL) was added to a −78° C. solution of LDA (6.7mL, 2.0M in THF, 13.5 mmol) in THF (30 mL). After 45 min, trimethylsilylchloride (2.0 g, 18.5 mmol) was added, and the mixture was slowly warmedto 0° C. The mixture was diluted with satd. NaHCO₃ solution (30 mL),extracted with Et₂O (2×30 mL), dried (MgSO₄) and concentrated. Theresidue was dissolved in THF (60 mL), and N-bromosuccinimide (2.6 g,14.7 mmol) was added portionwise. After 30 min, the mixture was dilutedwith saturated NH₄Cl solution (30 mL) and extracted with Et₂O (2×40 mL).The combined organic layers were dried (MgSO₄) and concentrated. Theresidue was purified via flash chromatography using 33:1 hexanes-Et₂O asthe eluent to provide 2-bromo-endo-6,9-ethanobicyclo[4.4.0]dec-7-enone(68) (1.44 g) as a light yellow oil, which was pure by ¹H-NMR and GC/MS.

Sodium azide (280 mg, 4.3 mmol) was added to a solution of2-bromo-endo-6,9-ethanobicyclo[4.4.0]dec-7-enone (68) (850 mg, 3.9 mmol)in DMF (20 mL). After 2 hours, the mixture was diluted with water (30mL) and extracted with Et₂O (2×40 mL). The combined organic layers weredried (MgSO₄) and concentrated. The residue was purified via flashchromatography using 20:1 hexanes:Et₂O as the eluent to provide2-azido-endo-6,9-ethanobicyclo[4.4.0]dec-7-enone (69) (469 mg) as anoil, which was pure by ¹H-NMR.

Triphenylphosphine (486 mg, 1.85 mmol) was added to a solution of2-azido-endo-6,9-ethanobicyclo[4.4.0]dec-7-enone (69) (310 mg, 1.42mmol) in THF (10 mL) and water (1 mL). After stirring for 12 hours, themixture was diluted with 6N HCl (10 mL) and the layers separated. Theorganic phase was extracted with 6N HCl (2×5 mL), and the combinedaqueous layers were concentrated to dryness to give the desired titlecompound 70 as a thick orange oil (500 mg), whose ¹H-NMR (DMSO-d₆) wasconsistent with the assigned structure.Isopropyl endo-2-Aminonorbornane-5-carboxylate (71) and Isopropylendo-2-Aminonorbornane-6-carboxylate (72).

These amines were prepared from isopropyl norborn-2-ene-5-carboxylate inthe same manner as described earlier (see Scheme 9).

General Procedure for Reductive Amination of Ketones to Amines.

Ketone (1 mmol), ammonium acetate (20 mmol) and 3A molecular sieves (2.8equivalents by weight) were mixed in anhydrous methanol in a dry flaskunder nitrogen atmosphere. Sodium cyanoborohydride (4 mmol) was addedand the resulting mixture was stirred at room temperature until thedisappearance of starting ketone as indicated by TLC analysis. Methanolwas stripped off from the reaction mixture under vacuum, and the residuedissolved in 6N HCl. After stirring for 15 min, the non-basic materialswere removed by extraction with diethyl ether. The pH of the aqueousphase was carefully raised to ˜8 using 50% aqueous NaOH, and the aminewas extracted with EtOAc (3 times). The EtOAc extracts were combined,washed with brine, dried (Na₂SO₄), filtered and concentrated to affordthe corresponding amine. The crude amine was generally pure and usedwithout further purification.

General Procedure for BOC-deprotection of Amines.

To an ice-cold solution of BOC-protected amine (1 mmol) in dry CH₂Cl₂ (1mL) were added triethylsilane (0.5 mL) and trifluoroacetic acid (1 mL).Progress of the reaction was monitored by disappearance of the startingmaterial (5 minutes to 1.5 hours). The reaction mixture was diluted withtoluene and concentrated. The residue was dissolved in water (10 mL) andEtOAc (20 mL), the pH was adjusted to ˜8 (aqueous NaHCO₃), and theorganic phase separated. The aqueous phase was extracted with EtOAc(2×15 mL). The organic phases were combined, washed with brine, dried(Na₂SO₄), filtered and concentrated to give the amine.Preparation of Amines 73 and 74.

These amines were prepared from the corresponding known ketodilactones(J. Org. Chem. 1998, 63, 9889-94) via the standard reductive aminationconditions described above. ¹H, ¹³C NMR and IR spectra were consistentwith the assigned structures.

Preparation of the Amines 77 and 78.

Preparation of these amines is shown in Scheme 16. The macrodilactone 75was prepared according to the procedure of J. Org. Chem. 1998, 63,9889-94. Thus, N-t-BOC-aspartic acid (2.33 g) was reacted with2-chloromethyl-3-chloropropene (1.25 g) and CS₂CO₃ (7.0 g) in DMF (1000mL) under the standard macrolactonization conditions reported in theabove reference to give 1.12 g (40% yield) of 75 as a glassy solid. Massspectrum (EI−) indicated [M−1]+ at (m/e) 284, while the ¹H, ¹³C NMR andIR spectra were consistent with the structure of 75.

To a solution of the alkene 75 (288 mg, 1.01 mmol) in dry EtOAc (6 mL)was added 10% Pd/carbon (60 mg). The resulting mixture was purged withnitrogen and stirred under 45 psi hydrogen pressure in a Parrhydrogenator for 2.5 h. The reaction mixture was purged with nitrogen,filtered and concentrated. The residue, upon purification by flashcolumn chromatography (silica gel, 7:3 mixture of hexane-EtOAc),afforded 91 mg (32% yield) of the reduced product 76. ¹H, ¹³C-NMR and IRspectra were consistent with the structure 76.

Removal of the BOC protecting group from 75 and 76, following thegeneral BOC-deprotection procedure described earlier, gave thecorresponding amines 77 and 78 respectively. ¹H, ¹³C-NMR and IR spectrawere consistent with the assigned structures.

Synthesis of the Phenyl Dilactone 81.

To an ice-cold (0° C.), well-stirred solution of phenylsuccinic acid(0.923 g, 5.2 mmol) and DMAP (0.064 g, 0.52 mmol) in dry CH₂Cl₂ (55 mL)was added dropwise under nitrogen a solution of BOC-serinol (Synthesis1998, 1113-1118) (1.0 g, 5.2 mmol) over 30 minutes. The resultingmixture was slowly warmed to room temperature, stirred for an additional12 hours, diluted with CH₂Cl₂ (40 mL), and extracted with saturatedaqueous sodium bicarbonate (3×10 mL). The basic extracts were combined,carefully acidified with 2N HCl, and extracted with EtOAc (3×20 mL). Thecombined EtOAc extract was washed with brine, dried (Na₂SO₄), filteredand concentrated to give a white foam (1.7 g). ¹H-NMR indicated a 1:1diastereomeric mixture of the acids 79.

To a well-stirred ice-cold suspension of acids 79 (1.00 g, 2.72 mmol)and triphenylphosphine (786 mg, 3.0 mmol) in dry THF (122 mL) was addeda solution of diethyl azodicarboxylate (0.52 g, 3.0 mmol) in THF (55 mL)drop-wise over 3 hours. The resulting mixture was slowly warmed to roomtemperature, stirred for an additional 5 hours, and concentrated toabout 5 mL. The residual mixture was diluted with EtOAc (50 mL) andwater (20 mL). The organic phase was separated, washed with aqueousNaHCO₃ (10 mL), brine (10 mL), dried (Na₂SO₄), filtered and concentratedto give an oily residue. Purification by flash chromatography (silicagel, hexanes) afforded 228 mg (22% yield) of a 1:1 mixture of dilactones80, m.p.=161-162° C. Mass spectrum (EI) indicated M+ at m/e 349.

Removal of the BOC protecting group under the standard BOC deprotectionconditions described earlier gave the amine 81.

Synthesis of the Dilactoneamines 84 and 85.

To a stirred solution of serinol (3.0 g, 15.7 mmol), pyridine (1.24 g,0.98 mol) and DMAP (0.19 g, 1.57 mmol) in dry CH₂Cl₂ (140 mL) was addeddropwise a solution of N-CBz aspartic anhydride (3.52 g, 14.13 mmol) indry THF (20 mL). After stirring for 2 h at room temperature, thereaction mixture was concentrated to a volume of about 10 mL and dilutedwith EtOAc (100 mL) and water (30 mL). The pH was adjusted to 8.5(aqueous NaHCO₃), and the aqueous phase was separated, acidified with 2NHCl to pH 3, and extracted with EtOAc (3×20 mL). The combined organicextract was washed with brine, dried (Na₂SO₄), filtered and concentratedto give 5.8 g of 82 as a foamy white material. ¹H-NMR spectra indicatedthat it was quite pure and contained a mixture of diastereomers.

To a solution of triphenylphosphine (3.60 g, 13.75 mmol) and1,3-diisopropylcarbodiimide (2.80 g, 13.75 mmol) in dry THF (1.15 L) wasadded dropwise over 3 hours a solution of the acid 82 (5.5 g, 12.5 mmol)in dry THF (100 mL). The resulting mixture was stirred for an additional6 hours, concentrated in vacuum to a volume of about 20 mL, and dilutedwith ether (200 mL) and water (100 mL). The organic phase was separatedand washed with 5% aqueous NaHCO₃ and brine, dried (Na₂SO₄), filteredand concentrated in vacuum. The oily residue was purified by flashcolumn chromatography to afford 1.3 g (23% yield) of the desireddilactones 83. Mass spectrum (ES−) indicated an m/e of 421 (M−1)+. ¹H,¹³C-NMR and IR spectra were consistent with the structure 83.

Dilactone 83 was deprotected under standard BOC deprotection conditionsto give the amine 84.

To a solution of the N-CBz-protected dilactone 83 (200 mg, 0.47 mmol) inEtOAc (10 mL) was added 10% Pd/C (40 mg), and the resulting mixture wasstirred under a balloon pressure of hydrogen gas for 12 hours. Thereaction mixture was purged with N₂, filtered through a sintered glassfunnel, and concentrated to give the amine 85 (126 mg). This crude aminewas used without further purification.Preparation of the Amines 86 and 88.

Syntheses of 2,6,6-trimethyl-2,4-cycloheptadienylamine (86) and2,3,6,6-tetramethyl-3-cycloheptenone (87), which is the precursor to theamine 88, are shown in Scheme 19. Thus, eucarvone (Can. J. Chem. 1974,52, 1352) was readily converted to the corresponding amine 86 using thetitanium isopropoxide/NaBH₄/Et₃N-mediated reductive amination proceduredescribed in Synlett 1999, 1781. Cu(I)-catalyzed Michael addition oftrimethylaluminum to eucarvone, using the procedure described inTetrahedron 1995, 51, 743-754, gave 2,3,5,5-tetramethyl-3-cycloheptenone(87). The latter was converted to2,3,5,5-tetramethyl-2-cycloheptenylamine (88) according to the generalprocedure of world patent WO 9927783.N-Methyl-N-(2-phenylethyl)-(1,5,5-trimethyl-3-aminocyclohexyl)carbamide(89).

1,5,5-trimethyl-3-oxo-1-cyclohexylcarboxylic acid (M. S. Ziegler and R.M. Herbst, J. Org. Chem. 1951, 16, 920) was coupled toN-Methyl-2-phenylethylamine using the standard HOAt, EDCI andDMAP-mediated coupling conditions to give[N-methyl-N-(2-phenylethyl)]-1,5,5-trimethyl-3-oxo-1-cyclohexylcarboxamideas a pale yellow oil. Mass spectrum indicated the parent ion at m/e 301.¹H and ¹³C-NMR spectra were consistent with this structure.

Amine 89 was prepared from this ketone according to the generalprocedure of world patent WO 9927783, by converting to the correspondingN-hydroxyoxime followed by hydrogenation in the presence of Raney® Ni.¹H-NMR of the amine indicated a 1:1 mixture of diastereomers.3-(3,3-Dimethylbutoxycarbonyl)-3,5,5-trimethylcyclohexylamine (90).

1,5,5-trimethyl-3-oxo-1-cyclohexylcarboxylic acid (3.0 g) (M. S. Zieglerand R. M. Herbst, J. Org. Chem. 1951, 16, 920) was treated with3,3-dimethylpentanol (1.84 g), DMAP (2.21 g) and1,3-diisopropylcarbodiimide (2.17 g) in CH₂Cl₂ (80 mL) under standardcoupling conditions to give 2.41 g (55% yield) of3-(3,3-dimethylbutoxycarbonyl)-3,5,5-trimethylcyclohexanone. Massspectrum (EI) indicated parent ion at m/e 268.

This ketone was converted to the title amine 90 according to the generalprocedure of world patent WO 9927783, by converting to the correspondingoxime followed by hydrogenation in the presence of Raney® Ni. ¹H-NMR ofthe amine 90 indicated a 1:1 mixture of diastereomers.

4-(4,6-bis-Trifluoromethyl-2-pyridyl)oxy-3,3,5,5-tetramethylcyclohexlamine(93).

Synthesis of this amine is shown in Scheme 20. Thus,4-hydroxy-3,3,5,5-tetramethylcyclohexyl-1,1-ethylene glycol acetal (900mg, 4.2 mmol) was dissolved in dry DMF (8.4 mL), the mixture was cooledto 0° C., and 35% (wt) oil suspension of KH (591 mg, 5.04 mmol) wasadded. After stirring the mixture for 1 hour, a solution of2-chloro-4,6-bis-trifluoromethyl-2-pyridine (1.48 g, 6.3 mmol) in DMF (2mL) was added dropwise. The mixture was stirred at 0° C. for 1 hour,then at room temperature for 12 hours, and carefully quenched withammonium chloride. Diethyl ether (100 mL) was added, and the organicphase was separated, washed with brine, dried (MgSO₄) and concentratedto a dark brown solid. Recrystallization from hot hexanes yielded 950 mg(53% yield) of4-(4,6-bis-trifluoromethyl-2-pyridyl)oxy-3,3,5,5-tetramethylcyclohexyl-1,1-ethyleneglycolacetal(91), m.p.=105-106° C.

The acetal 91 (900 mg) was dissolved in a 1:1:1 mixture (30 mL) of THF,dioxane and 2N HCl, and the resulting solution was stirred at roomtemperature for 12 hours, when GC indicated complete disappearance ofthe starting material. The mixture was diluted with water and diethylether (50 mL each), the organic phase was separated, washed with brine,dried (Na₂SO₄) and concentrated to give an oily residue. This residuewas chromatographed on silica gel (hexane-EtOAc, 5:1) to give 712 mg(96% yield) of ketone 92 as a colorless oil. Mass spectrum (EI)indicated parent ion m/e of 383.

Reductive amination of 92 to the title amine 93 was accomplishedaccording to the general procedure of world patent WO 9927783.

3-(2,3-Dichloropropyloxy)methyl-3,5,5-trimethylcyclohexylamine (97).

Synthesis of the amine 97 is shown in Scheme 21. Dichlorination of thealkene 94, according to the procedure of Tetrahedron Lett. 1991, 32,1831-4, yielded the acetal 95. The latter (500 mg) was dissolved in a1:1 mixture of THF and 2N HCl. The resulting solution was stirred atroom temperature for 1 hour, when TLC indicated that the startingmaterial had disappeared. The mixture was diluted with EtOAc and water(30 mL each), and the organic phase was separated and washed with brine,dried (Na₂SO₄), filtered and concentrated to give 383 mg of ketone 96 asan oil. ¹H-NMR was consistent with a diasteromeric mixture of isomers.Reductive amination following the standard procedure described earlierafforded the title amine 97.

3-Benzoyl-3,5,5-trimethylcyclohexylamine (100).

Preparation of this amine is shown in Scheme 22.3-Cyano-3,5,5-tetramethylcyclohexyl-1,1-ethyleneglycolacetal (98) (WorldPatent WO 9927783), upon reaction with phenyllithium followed by acidhydrolysis, afforded the diketone 99, which was converted to the titleaminoketone 100 according the procedure of the above patent.

5β-(2-Phenylethyl)-3β-methoxy-4β-methyl-4-nitro-cyclohexylamine (105).

Preparation of the amine 105 is shown in Scheme 23. Condensation ofnitroethane with dihydrocinnamaldehyde, according to the procedure ofBull. Chem. Soc. Jap. 1968, 41, 1441, gave the corresponding nitroalcohol 101. Dehydration of 101, according to the procedure ofSynthesis, 1982, 1017, followed by polymer supportedtriphenylphosphine-mediated isomerization (Tetrahedron Lett. 1998, 39,811-812), gave the alkene 103. Diels-Alder cycloaddition of 103 toDanishefsky's diene, according to the procedure of Tetrahedron Lett.2000, 41, 1717, yielded the ketone 104. The ketone 104 was converted tothe amine 105 according to the standard procedure of World Patent WO9927783.

3-Cyano-3,5,5-trimethylcyclohexylamine (106).

This compound was prepared (Scheme 24) by reductive amination of3-cyano-3,5,5-trimethylcyclohexanone according to the standard reductiveamination procedure described above. The mass spectrum (EI) indicatedparent ion m/e of 167.

3-Amino-5-phenylthiopyran (107).

This compound was prepared as shown in Scheme 25. Thus, to 0.96 g (5mmol) of 5-phenyl-3-thiopyranone (P. T. Lansbury, et al., J. Am. Chem.Soc. 1970, 92, 5649) in 50 mL of anhydrous methanol was added 7.7 g (100mmol) of ammonium acetate and 6.5 g of 3A molecular sieves. Afterstirring 30 minutes at room temperature, 1.25 g (20 mmol) of sodiumcyanoborohydride was added portionwise. After stirring 16 hours, themixture was gravity filtered, and the methanol was evaporated undervacuum. The residue was partitioned between ice/HCl and ether. Theacidic aqueous phase was extracted twice more with ether, then it wasmade basic with ice and 50% NaOH aqueous. The mixture was extracted withCH₂Cl₂, dried (MgSO₄), and evaporated to give 0.19 g (20%) of the titlecompound. GC/MS showed 100% purity with a molecular ion of 193.

4-(4-Trifluoromethyl)phenoxycyclohexylamine (109).

This compound was prepared according to Scheme 26. To a stirred solutionof sodium hydride (1.2 g, 0.05 mol) in 50 mL of DMF was added dropwiseover 10 minutes a solution of 1,4-dioxaspiro[4.5]decan-8-ol (7.5 g,0.047 mol) in 15 mL of DMF. The mixture was stirred at ambienttemperature for 30 minutes. 4-Fluorobenzotrifluoride (7.71 g, 0.047 mol)was added all at once and the reaction stirred at room temperature for 2hours and then overnight at 70° C. The reaction mixture was poured intocold water (700 mL) and the solution made slightly acidic by theaddition of 1N HCl. The mixture was filtered and the aqueous filtrateextracted with hexane (2×150 mL). The filtered solid was dissolved inthe hexane extracts and washed with water (50 mL). The solution wasdried over MgSO₄, filtered and concentrated to afford a white solid.This solid was recrystallized from methanol/water to give the pure ketal(8.6 g, 61%).

Silica gel (30 g) was suspended in 150 mL of CH₂Cl₂. To this suspensionwas added dropwise over 5 minutes 7 mL of a 12% HCl solution in water.The mixture was stirred vigorously to prevent clumping. A solution ofthe above ketal (8.0 g, 26.49 mmol) dissolved in 75 mL CH₂Cl₂ was addedand the reaction was stirred for 3 hours. The mixture was then filteredand the silica gel pad was washed with 500 mL CH₂Cl₂. The solvent wasevaporated to afford 5.8 g (86%) of 4-(4-trifluorophenoxy)cyclohexanone(108).

Reductive amination of ketone 108 according to the standard reductiveamination procedure described above, gave the title compound 109.

4-Benzoyloxy-3,3,5,5-tetramethylcyclohexylamine (111).

This compound was prepared following the procedure of Scheme 27. To astirred solution of 7,7,9,9-tetramethyl-1,4-dioxaspiro[4.5]decan-8-ol(0.37 g, 1.73 mmol) in 6 mL of THF cooled to 0° C. was added n-BuLi(2.5M in hexanes, 1.73 mmol, 0.7 mL) dropwise. The reaction was stirredfor 10 min. Benzoyl chloride (1.73 mmol, 0.2 mL) was then added, and thereaction was allowed to warm to room temperature and stirred overnight.The reaction mixture was poured into 50 mL 0.5N NaOH and extracted withether (3×20 mL). The ethereal layer was dried over MgSO₄, filtered andconcentrated. The residue was purified by radial chromatography using4:1 hexane-EtOAc as the eluent. Thus obtained was 0.55 g (˜100%) of thebenzoyloxyketal.

Silica gel (2.2 g) was suspended in 10 mL of CH₂Cl₂. To this suspensionwas added dropwise over 5 minutes 0.5 mL of a 12% HCl solution in water.The mixture was stirred vigorously to prevent clumping. A solution ofthe above benzoyloxy ketal dissolved in 5 mL CH₂Cl₂ was added and thereaction was stirred for 3 hours. The mixture was then filtered and thesilica gel pad was washed with 100 mL CH₂Cl₂. The solvent was evaporatedto afford 0.46 g (90%) of the benzoyloxycyclohexanone 110 as a clearoil.

To a stirred solution of the benzoyloxycyclohexanone 110 (0.46 g, 1.68mmol) in 4 mL of methanol was added all at once a solution ofhydroxylamine hydrochloride (0.23 g, 3.25 mmol) and potassium acetate(0.32 g, 3.25 mmol) in 4 mL of water. The reaction was stirred at roomtemperature overnight. Water (20 mL) was added and the resulting mixtureextracted with ether (3×10 mL). The ether extracts were combined, washedwith saturated NaHCO₃ (1×20 mL) and brine (1×15 mL). The ethereal layerwas dried over MgSO₄, filtered and concentrated to give the desiredoxime (0.39 g, 80%) as a mixture of E and Z isomers.

Raney® Nickel (0.8 g wet weight, Aldrich Chemical Co.) in a 500 mL Parrpressure bottle was washed with water (3×20 mL) then ethanol (3×20 mL),the wash solvent being decanted each time. To this washed catalyst wasadded a solution of the oxime (0.39 g, 1.35 mmol) in anhydrous ethanol(30 mL). Some heating of this solution was required for dissolution. Theresulting mixture was saturated with ammonia by bubbling ammonia gasthrough the solution for 1 minute. This solution was placed under ahydrogen atmosphere (initial hydrogen pressure=50 psi) on a Parr shakerand shaken for 7 hours. The reaction mixture was then filtered through apad of Celite® and the solvent was evaporated to yield a nearlycolorless liquid (0.37 g, quantitative yield). The proton NMR and GC/MSwere consistent with this material being a diastereomeric (4:1 ratio)mixture of the title amine 111. This material was used as is with noadditional purification.

4-Amino-2,2,6,6-tetramethylcyclohexyl-6-chloro-2-pyridinecarboxylate(113).

This compound was synthesized as shown in Scheme 28. To a stirredsolution of 7,7,9,9-tetramethyl-1,4-dioxaspiro[4.5]decan-8-ol (0.32 g,1.50 mmol) in 5 mL of THF cooled to 0° C. was added n-BuLi (2.5M inhexanes, 1.50 mmol, 0.6 mL) dropwise. The mixture was stirred for 10minutes. 6-Chloropicolinoyl chloride (1.50 mmol, 0.26 g) was then addedas a solution in 1 mL THF and then the reaction was allowed to warm toroom temperature. The solution solidified, so an additional 5 mL of THFwas added and the reaction stirred overnight. The reaction mixture waspoured into 40 mL 0.5N NaOH and extracted with ether (3×20 mL). Theethereal layer was dried over MgSO₄, filtered and concentrated. ProtonNMR revealed the expected product together with starting material in1.6:1 ratio. These compounds could not be separated by silica gelchromatography so the mixture was carried on to the next step andpurified there.

Silica gel (1.4 g) was suspended in 10 mL of CH₂Cl₂. To this suspensionwas added dropwise over 5 minutes 0.3 mL of a 12% HCl solution in water.The mixture was stirred vigorously to prevent clumping. A solution ofthe above mixture dissolved in 5 mL CH₂Cl₂ was added and the reactionwas stirred for 3 hours. The mixture was then filtered and the silicagel pad was washed with 100 mL CH₂Cl₂. The solvent was evaporated toafford an oil. Precipitation of the desired picolinic ester 112 waseffected by adding 10 mL of 4:1 hexane-EtOAc solution. The resultingsolid was filtered and washed with 10 mL of 4:1 hexane-EtOAc. Thehexane-EtOAc washings were combined and evaporated to yield an oil. Theabove procedure was repeated 3 times to afford the picolinic ester 112as a white solid (214 mg, 46% for two steps). Proton NMR and GC/MSshowed the desired product in >95% purity.

A mixture of this ester (200 mg, 0.65 mmol), titanium(IV) isopropoxide(1.30 mmol, 0.38 mL), ammonium chloride (1.30 mmol, 70 mg) andtriethylamine (1.30 mmol, 0.18 mL) in absolute ethanol (10 mL) wasstirred under nitrogen at ambient temperature for 12 hours. Sodiumborohydride (0.97 mmol, 40 mg) was then added and the resulting mixturewas stirred for an additional 8 hours at ambient temperature. Thereaction was then quenched by pouring into aqueous ammonia (20 mL, 2.0M), and the resulting solution was extracted with ether (3×20 mL). Thecombined ether extracts were extracted with 2N HCl (2×20 mL) to separatethe non-basic materials. The acidic solution was washed once with ether(20 mL), and then treated with aqueous sodium hydroxide (2N) to pH10-12, and extracted with EtOAc (3×20 mL). The combined EtOAc washingswere dried over MgSO₄, filtered and concentrated to afford an oil. Thismaterial was consistent with a 6:1 diastereomeric mixture of the titlecyclohexylamines. Proton NMR and GC/MS showed the desired product in˜75% purity. This mixture of amines was used as is without furtherpurification.trans-2-Thiomethylcyclohexylamine.

This amine was prepared from cyclohexene using the azasulfenylationtechnology of B. M. Trost and T. Shibata, J. Am. Chem. Soc. 1982, 104,3225.

4-Phenylthiocyclohexylamine (115).

This compound was prepared following the procedure shown in Scheme 29.To stirred solution of 4-phenylthiocyclohexanone (V. K. Yadav and D. A.Jeyaraj, J. Org. Chem. 1998, 63, 3474) (1.20 g, 5.83 mmol) in 20 mL ofmethanol was added all at once a solution of benzyloxyaminehydrochloride (1.80 g, 11.22 mmol) and potassium acetate (1.10 g, 11.22mmol) in 20 mL of water. The reaction was stirred at room temperatureovernight. Water (60 mL) was added and the resulting mixture extractedwith ether (3×40 mL). The ether extracts were combined, washed withsatd. NaHCO₃ (1×50 mL) and brine (1×40 mL). The ethereal layer was driedover MgSO₄, filtered and concentrated to give an oil. This material waspurified via radial chromatography (9:1 hexane-EtOAc) to afford thecorresponding O-benzyloxime 114 (1.72 g, 95%) as a mixture of E and Zisomers.

Lithium aluminum hydride (5.08 mmol, 0.19 g) was suspended in 10 mL ofanhydrous ether and cooled to 0° C. The O-benzyloxime 114, dissolved in5 mL of ether, was added dropwise, and the reaction was allowed to warmto room temperature and stirred for 4 hours. Excess lithium aluminumhydride was destroyed by careful, simultaneous addition of water (0.2mL) and 1N NaOH (0.2 mL). The mixture was filtered and the salts washedwith 50 mL of ether. The solvent was evaporated to afford 0.62 g (93%)of the title amine 115 as an oil. Proton NMR and GC/MS revealed theproduct to be a 1.3:1 ratio of diastereomeric amines in >95% purity.

3-{[3-(Trifluoromethyl)-2-pyridinyl]sulfanyl}-cyclohexylamine (117).

This amine was prepared following the method shown in Scheme 30. To astirred solution of 2-cyclohexen-1-one (0.44 mL, 4.58 mmol) and2-mercapto-5-trifluoromethylpyridine (0.82 g, 4.58 mmol) in 20 mL CH₂Cl₂at ambient temperature was added bismuth trichloride (60 mg, 0.18 mmol).The reaction was stirred at room temperature overnight and concentrated.The residue was purified via radial chromatography using 4:1hexane-EtOAc as the eluent to afford 1.12 g (89%) of the conjugateaddition product 2-(3-oxo-cyclohexylthio)-5-trifluoromethylpyridine(116).

To a stirred solution of 116 (0.26 g, 0.95 mmol) in 3 mL of methanol wasadded all at once a solution of benzyloxyamine hydrochloride (0.29 g,1.83 mmol) and potassium acetate (0.18 g, 1.83 mmol) in 3 mL of water.The reaction was stirred at room temperature overnight. Water (10 mL)was added and the resulting mixture extracted with ether (3×10 mL). Theether extracts were combined, washed with saturated NaHCO₃ (1×15 mL) andbrine (1×15 mL). The ethereal layer was dried over MgSO₄, filtered andconcentrated to give an oil. This material was purified via radialchromatography (9:1 hexane-EtOAc) to afford the separated oximes (0.32g, 89%). The E-isomer (R_(f)=0.33) and Z-isomer (R_(f)=0.25) showedconsistent proton NMR and GC/MS spectral characteristics.

Lithium aluminum hydride (1.33 mmol, 50 mg) was suspended in 3 mL ofanhydrous ether and cooled to 0° C. The combined oximes, dissolved in 1mL of ether, was added dropwise and the reaction was allowed to warm toroom temperature and stirred for 4 hours. Excess lithium aluminumhydride was destroyed by careful, simultaneous addition of water (50 μL)and 1N NaOH (50 μL). The mixture was filtered and the salts washed withether to a volume of 100 mL. The ether solution was extracted with 2NHCl (2×50 mL) to separate the non-basic materials. The acidic aqueoussolution was washed once with ether (50 mL), then treated with aqueoussodium hydroxide (2M) to pH 10-12, and extracted with ether (3×50 mL).The ethereal layer was dried over MgSO₄, filtered and concentrated toafford 121 mg (52%) of the desired title amine 117 as an oil. Proton NMRand GC/MS revealed the product to be a 1.3:1 ratio of diastereomericamines in >95% purity.

1-(5-Amino-1,3,3-trimethylcyclohexyl)-4-phenyl-1-butanone (120).

Synthesis of this amine was accomplished by the method depicted inScheme 31. A suspension of naphthalene (1.23 g, 9.57 mmol) and lithiumgranules (67 mg, 9.57 mmol) in 10 mL of THF at ambient temperature wasstirred overnight under nitrogen. This lithium naphthalide solution wascooled to −60° C. and phenyl 3-phenylpropyl sulfide (1.1 g, 4.78 mmol)was added. The reaction was warmed to −20° C. to ensure completereaction and then recooled to −60° C. A solution of7-cyano-7,9,9-trimethyl-1,4-dioxaspiro[4.5]decane (0.5 g, 2.39 mmol) in5 mL THF was added and the solution warmed to 0° C. and stirred for 2hours at that temperature. The reaction was quenched by the addition of10 mL of saturated ammonium chloride solution and then treated with 2NHCl to pH ˜4 and stirred at room temperature overnight. The mixture wasextracted with ether (3×30 mL), dried over MgSO₄, filtered andevaporated. The residue was purified via radial chromatography using 6:1hexane-EtOAc as the eluent. Thus obtained was a 1:3 mixture of3-(2-oxo-4-phenylbutyl)-3,5,5-trimethylcyclohexanone 118 (136 mg,R_(f)=0.18) and its ketal (509 mg, R_(f)=0.33), the product of anincomplete hydrolysis. The total yield for the addition of1-lithio-3-phenylpropane to the nitrile was calculated to be 85%.

Silica gel (1.82 g) was suspended in 10 mL of CH₂Cl₂. To this suspensionwas added dropwise over 5 minutes 0.41 mL of a 12% HCl solution inwater. The mixture was stirred vigorously to prevent clumping. Asolution of the above ketal dissolved in 2 mL CH₂Cl₂ was added and thereaction was stirred for 3 hours. The mixture was then filtered and thesilica gel pad was washed with 50 mL CH₂Cl₂. The solvent was evaporatedto afford 0.48 g (100%) of3-(1-oxo-4-phenylbutyl)-3,5,5-trimethylcyclohexanone (118) as a clearoil consistent with its NMR and GC/MS properties.

To a stirred solution of this bis-ketone (0.62 g, 2.17 mmol) in 7 mL ofmethanol was added all at once a solution of hydroxylamine hydrochloride(0.16 g, 2.28 mmol) and sodium acetate (0.25 g, 3.03 mmol) in 7 mL ofwater. The reaction was stirred at room temperature for 1 hour. Water(20 mL) was added and the resulting mixture extracted with ether (3×20mL). The ether extracts were combined, washed with saturated NaHCO₃(1×20 mL) and brine (1×20 mL). The ethereal layer was dried over MgSO₄,filtered and concentrated to give the desired mono-oxime 119 (0.57 g,87%) as a mixture of E and Z isomers.

Raney® Nickel (0.8 g wet weight, Aldrich Chemical Co.) in a 500 mL Parrpressure bottle was washed with water (3×20 mL) then ethanol (3×20 mL),the wash solvent being decanted each time. To this washed catalyst wasadded a solution of the oxime 119 (0.57 g, 1.89 mmol) in anhydrousethanol (40 mL). The resulting mixture was saturated with ammonia bybubbling ammonia gas through the solution for 1 minute. This solutionwas placed under a hydrogen atmosphere (initial hydrogen pressure=50psi) on a Parr shaker and shaken for 7 hours. The reaction mixture wasthen filtered through a pad of Celite® and the solvent was evaporated toyield an oil (0.43 g, 80%). Analysis by GC/MS showed a 1:1diastereomeric mixture of the title amines 120, along with a minorunidentified byproduct. This mixture of amines was used directly as iswithout further purification.

2-Benzyl-6-methyl-4-pyranylamine (122).

This amine was prepared according to Scheme 32. To 0.37 g (1.8 mmol) of2-benzyl-6-methyl-4-pyranone (G. Piancatilli, et. al., Synthesis, 1982,248) was added 0.22 g (3.1 mmol) of hydroxylamine hydrochloride and 0.16g (2 mmol) of sodium acetate in 10 mL of methanol. After stirringovernight, the mixture was partitioned between CH₂Cl₂ and water. Theorganic phase was dried and evaporated. The oily residue solidified uponstanding at room temperature to give 0.4 g (99%) of the desired oxime121 as a Z/E isomer mixture 1:1 by GC/MS with a molecular ion of 219,and that was used as is in the reduction reaction below.

To 0.4 g of 2-benzyl-6-methyl-4-pyranone oxime (121) (1.8 mmol) in 50 mLof 95% ethanol was added 0.8 g (wet weight) of Raney® nickel that hadbeen washed with water 3 times and ethanol 3 times. The mixture wasplaced under 41 psig of hydrogen in a Parr Shaker for 32 hours. Afterventing, the mixture was gravity filtered and evaporated under vacuum.The residue was partitioned between CH₂Cl₂ and aqueous sodium carbonatesolution. The organic phase was dried and evaporated under vacuum togive 0.19 g of a mixture of the desired title amine 122 plus oxime 121in a 2:1 mixture by GC/MS analysis. The mixture was used as is withoutfurther separation.1-Benzoyl-4-aminopiperidine.

This compound was prepared by the method of Bhattacharyya, et al.,SynLett, 1999, 11, 1781.

1-(4-Methylbenzyl)-4-piperidinylamine (125).

Synthesis of this compound was accomplished according to Scheme 33. To5.05 g (50 mmol) of 4-hydroxypiperidine and 7.08 g (50 mmol) ofp-methylbenzyl chloride in 25 mL of tert-butanol was added excess solidpotassium carbonate, and the mixture was heated on a steam bath for 3 h.The mixture was cooled to room temperature and partitioned between etherand water. The organic phase was extracted with cold dilute HCl, and theacidic aqueous phase was extracted with ether twice. The aqueous phasewas made basic with ice and 50% aqueous NaOH and extracted with ether.The ether phase was washed with dilute aqueous sodium bicarbonatesolution, brine, dried, and evaporated under vacuum to give 5.3 g (52%)of 1-(4-methylbenzyl)-4-hydroxypiperidine (123) as an oil. GC/MS showed100% purity with a molecular ion of 205.

To 2.8 mL (32 mmol) of oxalyl chloride in 75 mL of CH₂Cl₂ at −78° C. wasadded 4.6 mL (64 mmol) of DMSO. To this mixture was added 5.3 g (26mmol) of 1-(4-methylbenzyl)-4-piperidinol 123 in 10 mL of CH₂Cl₂, andthe mixture was stirred 5 min in the cold. The mixture was quenched with18 mL (129 mmol) of triethylamine and allowed to come to roomtemperature, and saturated aqueous ammonium chloride was added. Theorganic phase was washed with water and brine, dried, and evaporated togive 4.27 g (81%) of 1-(4-methylbenzyl)-4-piperidinone (124), which wasused as is without further purification. GC/MS showed 100% purity with amolecular ion of 203.

To 4.25 g (21 mmol) of 1-(4-methylbenzyl)-4-piperidinone 124 in 200 mLof anhydrous methanol was added 32.2 g (420 mmol) of ammonium acetateand 25 g of 3A molecular sieves. After stirring 30 min, 5.25 g (84 mmol)of sodium cyanoborohydride was added portionwise. After stirring 16hours, the mixture was gravity filtered and the methanol evaporatedunder vacuum. The residue was partitioned between ether and ice/HCl. Theacidic aqueous layer was extracted twice with ether, made basic with 50%aqueous NaOH and ice, and extracted with CH₂Cl₂ to give 2.1 g (48%) ofthe title amine 125 as a thick oil. GC/MS showed a molecular ion of 204.The product was used as is without further purification.

1-(3-Trifluoromethylbenzyl)-4-piperidinylamine (127).

Prepared according to Scheme 34. To 0.8 g (3.1 mmol) of1-(3-trifluoromethylbenzyl)-4-piperidone [prepared in the same manner as1-(4-methylbenzyl)-4-piperidinone) 123] in 7 mL of pyridine was added0.22 g (3.1 mmol) of hydroxylamine hydrochloride, and the mixture wasstirred overnight. The mixture was evaporated under vacuum and theresidue partitioned between ether and dilute aqueous sodium bicarbonate.The organic phase was dried and evaporated under vacuum to give 0.52 g(62%) of the oxime as an oil, which was used as is in the hydrogenationstep below. GC/MS showed a molecular ion of 272.

To 0.5 g (2 mmol) of this oxime in 75 mL of ethanol was added 0.5 g (wetweight) of Raney® nickel that had been washed 3 times each with waterand ethanol. Ammonia gas was bubbled into the mixture for severalminutes and all was placed under 45 psig of hydrogen in a Parr shakerfor 7 hours. The vessel was vented and the mixture gravity filtered. Theresidue was dissolved in ether, filtered, and evaporated to give 0.43 g(81%) of the title amine 127, which was used as is without furtherpurification. GC/MS indicated a single peak with a molecular ion of 258.

cis/trans-2-Methyl-3-tetrahydrofurylamine (128).

This amine was obtained following the method of Scheme 35. To 1.15 g (10mmol) of 2-methyltetrahydrofuran-3-one oxime (prepared via standardprocedures from commercially available 2-methyltetrahydrofuran-3-one) in50 mL of methanol was added 1 g (wet weight) of Raney® nickel that hadbeen washed 3 times each with water and ethanol, and placed in a Parrshaker under 44 psig of hydrogen. After 18 hours, the mixture was ventedand gravity filtered. The methanol was evaporated under vacuum, and theresidue was taken up in ether and dried. The ethereal phase wasevaporated under vacuum to give 0.6 g (59%) of the title amine 128 as acis/trans mixture. The GC/MS showed 41% with a molecular ion of 101 and59% with a molecular ion of 101. The amine mixture was used as iswithout further purification.

2-Benzyl-2,6-dimethyl-4-pyranylamine (133).

This amine was obtained following the procedure depicted in Scheme 36.To 4.88 g (19.7 mmol) of 3-trimethylsilyoxybutyric acid trimethylsilylester in 40 mL of CH₂Cl₂ at −78° C. was added 2.4 g (18 mmol) ofphenylacetone and 1 drop of trimethylsilyl triflate. The mixture wasallowed to stand in the cold for 2 days, then was quenched with 0.5 mLof pyridine and allowed to come to room temperature. The organic phasewas washed with dilute aqueous sodium bicarbonate solution, dried, andevaporated under vacuum. The residue was distilled under vacuum to give2.89 g (67%) of 2-benzyl-2,6-dimethyl-4-methylene-1,3-dioxan-4-one(129), b.p. 125-32 @ 0.6 mm. GC/MS showed two isomers, each with a basepeak of 134 (phenylacetone).

To 1.5 g (6.8 mmol) of2-benzyl-2,6-dimethyl-4-methylene-1,3-dioxan-4-one (129) under nitrogenwas added 2.9 g (13.9 mmol) of bis-(cyclopentyl)-bis-methyl titanocenein 20 mL dry THF. The mixture was heated at reflux for 16 hours. Thereaction mixture was cooled to room temperature and quenched with excessether. The entire mixture was filtered through a silica gel bed withether as the eluent. The filtrate was evaporated and chromatographed onsilica gel with EtOAc and hexane (1:4) containing 0.2% triethylamine.The product-containing fractions were evaporated and slurried inpetroleum ether and filtered under vacuum to give 1.2 g of a solid.GC/MS showed a mixture of approximately 3:1 ratio of2-benzyl-2,6-dimethyl-4-methylene-1,3-dioxane (130) with a molecular ionof 218, and starting material 129. The mixture was used as is in therearrangement below.

To 1.2 g (5.5 mmol) of this mixture in 5 mL of toluene under nitrogenwas added 10.99 mL (11 mmol) of tri-isobutyl aluminum hydride at −78° C.The reaction was allowed to stand in the cold for 16 hours and thenquenched with a few drops of water. The mixture was allowed to come toroom temperature, and excess saturated aqueous ammonium chloride wasadded. The mixture was extracted with excess CH₂Cl₂, a difficultseparation from the aluminum salts. The organic layer was dried andevaporated to give 1.1 g (90%) of 2-benzyl-2,6-dimethyl-4-hydroxypyranol(131) as a 75:25 isomer mixture (by GC/MS).

To 1.1 g (5 mmol) of 131 in 10 mL of CH₂Cl₂ was added 1.6 g (7.5 mmol)of pyridinium chlorochromate portionwise with magnetic stirring. After 1hour at room temperature, ether was added and the mixture was filteredthrough a silica gel bed and washed through with ether. The filtrate wasevaporated to give 0.88 g (80%) of 2-benzyl-2,6-dimethyl-4-pyranone(132). GC/MS showed 99% purity with a base peak of 127 (M-benzyl). Theisomer mixture was used as is in the reductive amination below.

To 0.88 g (4 mmol) of 132 in 40 mL of anhydrous methanol was added 6.16g (80 mmol) of ammonium acetate and 5g of 3A molecular sieves. Afterstirring 45 min at room temperature, 1.02 g (16 mmol) of sodiumcyanoborohydride was added portionwise with magnetic stirring. Themixture was gravity filtered, and the methanol evaporated under vacuum.The residue was partitioned between ether and dilute cold HCl. Theaqueous phase was extracted with ether twice, then it was made basicwith ice and 50% aqueous NaOH. The product was extracted with CH₂Cl₂,dried, and evaporated to give 0.43 g (49%) of a two component isomermixture of the title amine 133. GC/MS showed 58% with a molecular ion of128 and 42% with a molecular ion of 128.

1-(3-Phenylpropionyl)-4-aminopiperidine (136).

This amine was synthesized in accordance with the method of Scheme 37.To 4 g (40 mmol) of 4-hydroxypiperidine in 20 mL of toluene was addedphenylpropionyl chloride (derived from 6 g (40 mmol) of phenylpropionicacid in excess thionyl chloride). To the mixture was added excess 2Naqueous NaOH. After stirring 24 hours, the toluene layer was discardedand the aqueous phase was extracted with CH₂Cl₂, dried, and evaporatedunder vacuum to give 3.63 g (39%) of1-(3-phenylpropionyl)-4-hydroxypiperidine (134). GC/MS indicated 100%purity with a molecular ion of 233.

To 1.68 mL of oxalyl chloride (19.2 mmol) in 35 mL of CH₂Cl₂ at −78° C.was added 2.73 mL (38.5 mmol) of dry DMSO in 5 mL of CH₂Cl₂. After theaddition, 3.6 g (15.4 mmol) of 1-(3-phenylpropionyl)-4-hydroxypiperidine134 in 5 mL of CH₂Cl₂ was added, and the mixture was stirred for 5 minin the cold. 10.73 mL (77 mmol) of triethylamine in 5 mL of CH₂Cl₂ wasadded, and the mixture was allowed to come to room temperature. Themixture was quenched with saturated aqueous ammonium chloride solution.The organic phase was washed with water twice, with saturated brine,dried, and evaporated under vacuum to give 3.2 g (89%) of1-(3-phenylpropionyl)-4-ketopiperidine (135). GC/MS showed 100% puritywith a molecular ion of 231.

To 3.2 g (13.8 mmol) of 135 in 125 mL of anhydrous methanol was added21.3 g of ammonium acetate and 20 g of 3A molecular sieves. Afterstirring 30 min, 3.47 g (55.2 mmol) of sodium cyanoborohydride was addedportionwise with stirring. After 3 hours, the mixture was gravityfiltered, and the methanol evaporated under vacuum. The residue waspartitioned between ice/HCl and ether. The acidic aqueous phase wasextracted twice more with ether. The aqueous phase was made basic withice and 50% aqueous NaOH. The mixture was extracted with CH₂Cl₂, dried,and evaporated under vacuum to give 1.5 g (47%) of the title amine 136.GC/MS indicated 100% purity with a molecular ion of 232.

Preparation of Amine 139.

Synthesis of this amine is shown in Scheme 38. A screw cap teflon tubewas charged with 137 (M. Shimano et al., Tetrahedron, 1998, 54, 12745)(0.80 g, 1.21 mmol) and 6 mL of pyridine. The solution was cooled to 0°C. and treated with 1.1 mL of HF-pyridine complex and the solutionwarmed to room temperature and stirred for 17 hours. An additional 1.1mL of HF-pyridine was then added and the reaction stirred for anadditional 30 hours. This mixture was poured into a stirred ice-coldsolution of 40 mL 1N HCl and 20 mL 1:1 hexane-diethyl ether. The layerswere separated and the aqueous layer was extracted with 1:1hexane-diethyl ether (2×20 mL). The combined organic layers were washedwith ice-cold 1N HCl (1×20 mL) and brine (1×20 mL). The solution wasdried over MgSO₄, filtered and concentrated. The crude product waspurified via radial chromatography (3:1 hexane-EtOAc) to give 282 mg ofthe hydroxyester (plus a minor impurity) which was carried directly tothe next step.

To a stirred solution of the crude hydroxyester (282 mg, 0.48 mmol) inpyridine cooled to 0° C. was added dropwise isobutyryl chloride (0.2 mL,1.92 mmol). The cooling bath was removed and the mixture stirred for 5hours. Water (2 mL) was added and the mixture stirred an additional 30minutes. The solution was extracted with ether (3×10 mL). The ethereallayer was washed successively with ice cold 1N HCl (2×10 mL), saturatedNaHCO₃ (1×10 mL) and brine (1×10 mL). The solution was dried over MgSO₄,filtered and concentrated. The crude product was purified via radialchromatography (4:1 hexane-EtOAc) to give 171 mg of the isobutyryl ester138 (23% overall for two steps).

The BOC group of this ester was removed following the standardBOC-deprotection conditions described earlier to afford the desiredamine 139.

Preparation of Amine 145.

This amine was prepared as depicted in Scheme 39. The hydroxyester 140(M. Shimano et al., Tetrahedron, 1998, 54, 12745) (6.27 mmol) wasdissolved in 15 mL DMF and cooled to 0° C. To this solution was addedsuccessively DMAP (1.53 g, 12.53 mmol), EDCI (1.8 g, 9.40 mmol) andN-BOC-O-Bn-(L)-threonine (2.52 g, 8.15 mmol). The reaction was warmed toroom temperature and stirred overnight. The solution was poured into arapidly stirred mixture of 30 mL ice cold 0.5N HCl and 50 mL 4:1hexane-ether. The layers were separated and the aqueous layer wasextracted with 4:1 hexane-ether (1×30 mL). The combined organic layerswere washed with 0.5N HCl (1×20 mL) and brine (2×20 mL). The solutionwas dried over MgSO₄, filtered and concentrated. The crude material waschromatographed on silica gel (150 g) using 1.25 L of 3:1 CH₂Cl₂-hexanesto elute anisaldehyde followed by 65:10:25 CH₂Cl₂-ether-hexanes to elutethe coupled product 141 (3.95 g, 88%).

A mixture of the benzyl ether 141 (1.32 g, 1.84 mol) and 200 mg 10% Pd/Cin 25 mL of EtOAc was shaken in a Parr apparatus under 50 psi ofhydrogen pressure for 5 hours. The mixture was filtered through a pad ofCelite® and concentrated to afford the hydroxy acid 142 (680 mg, 70%),quite pure by NMR analysis.

To a stirred solution of hydroxyacid 142 (1.54 g, 2.86 mmol) and benzylbromide (1.5 mL, 12.29 mmol) in 7 mL DMF was added solid sodiumbicarbonate (1.2 g, 14.27 mmol). The mixture was stirred at roomtemperature for 24 hours, then was partitioned between 25 mL water and10 mL 4:1 hexanes-ether. The layers were separated and the aqueous layerwas extracted with 4:1 hexane-ether (2×10 mL). The combined organiclayers were washed with 0.1N NaOH (1×10 mL) and water (1×10 mL). Thesolution was dried over MgSO₄, filtered and concentrated. The crudematerial was purified via radial chromatography (4:1 hexane-EtOAc) togive 1.04 g (60%) of the hydroxybenzyl ester 143.

To a stirred solution of ester 143 (840 mg, 1.34 mmol) and aceticanhydride (1.0 mL, 10.68 mmol) in 7 mL pyridine was added DMAP (40 mg,0.67 mmol). The reaction was stirred at room temperature for 4 hours anddiluted with 80 mL EtOAc. This solution was washed successively withsaturated CuSO₄ (3×30 mL), 1N HCl (1×30 mL), saturated NaHCO₃ (1×30 mL)and brine (1×30 mL). The solution was dried over MgSO₄, filtered andconcentrated to yield 0.9 g (100%) of acetate 144, quite pure byspectral analysis. The acetate 144 was converted via similar steps tothose described earlier to afford the amine 145.

Preparation of 2,3,4-Tri-O-alkyl-beta-D-xylopyranosylamine 147c, d, e.

Synthesis of these amines is shown in Scheme 40. To a stirred solutionof triacetoxy-2-azidoxylopyranosyl azide 146 (Acros Chemical Co.) inCH₃OH at room temperature was added 1.1 mL (1.06 mmol) of a 1.0 Msolution of sodium methoxide in methanol. The reaction was stirredovernight and neutralized with 5×8-100 acidic resin (˜0.6 g). Thesolution was filtered and concentrated. The azidotriol 147a obtained wasused directly in the next step.

The crude triol 147a was dissolved in 15 mL DMF, and NaH (60%dispersion, 0.53 g, 13.28 mmol) was added in four portions over 15minutes. The reaction was stirred for 30 minutes at room temperature,allyl bromide (2.7 mL, 33.20 mmol) was added, and the mixture stirredovernight. Saturated ammonium chloride (10 mL) was carefully addedfollowed by 50 mL of water. The aqueous solution was extracted withEtOAc (3×30 mL). The organic layer was washed successively with water(4×30 mL) and brine (2×30 mL). The solution was dried over MgSO₄,filtered and concentrated. The crude material was purified via radialchromatography (6:1 hexane-EtOAc) to give 753 mg (77%) of thetri-O-n-allyl-2-azidoxylopyranose 147b.

The resulting azide and allyl moieties were reduced by stirring with 150mg of 10% Pd/C in 40 mL EtOAc under 1 atmosphere of hydrogen for 4hours. The resulting solution was filtered through a pad of Celite® andevaporated to afford a quantitative yield of the title amine 147c.

The preparation of amine 147d was similar to that of 147c, except usingbenzyl bromide in the alkylation step, followed by reduction of theazide to the amine as described above.

Similar hydrogenation of azide 146 with 10% Pd/C in EtOAc under 1atmosphere of hydrogen afforded amine 147e.Preparation of 2,3,4-Tri-O-acetyl-beta-L-fucopyranosyl Amine (148).

To a solution of 2,3,4-Tri-O-acetyl-beta-L-fucopyranosyl azide (Acros)(750 mg, 2.38 mmol) in 40 mL of EtOAc was added 120 mg of 10% Pd/C. Thissolution was stirred under an atmosphere of hydrogen gas (1 atm) for 3hours. The mixture was filtered through a pad of Celite® and the pad waswashed with EtOAc (25 mL). The solution was evaporated to afford thedesired amine 148 (688 mg, 100%).Preparation of1,3,4,6-Tetra-O-acetyl-2-amino-2-deoxy-alpha-D-glucopyranose (149).

To a solution of1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-alpha-D-glucopyranose (TCI-US)(300 mg, 0.80 mmol) in 25 mL of EtOAc was added 180 mg of 10% Pd/C. Thissolution was stirred under an atmosphere of hydrogen gas (1 atm) for 3hours. The mixture was filtered through a pad of Celite® and the pad waswashed with EtOAc (20 mL). The solution was evaporated to afford thedesired amine 149 (282 mg, 100%).Preparation of Benzyl and Methyl3-Amino-trideoxy-L-arabino-hexopyranosides 150a and 150b.

These amines were synthesized via the method of L. Daley, et al., Synth.Commun. 1998, 28, 61.

Preparation of Amine 153.

This amine was prepared as shown in Scheme 41.[(3S,7R,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2,6-dioxo-[1,5]dioxonane-3-yl]-carbamicacid tert-butyl ester (151) was prepared as described by M. Shimano etal., Tetrahedron, 1998, 54, 12745. To a stirred solution of this ester(120 mg, 0.30 mmol) in pyridine (5 mL) was slowly added methacryloylchloride (0.10 mL, 1.0 mmol) over 5 minutes. The resulting mixture wasstirred at room temperature under a N₂ atmosphere overnight. Thereaction mixture was partitioned between EtOAc (75 mL) and 1N HCl (50mL). The organic layer was washed with water then saturated NaCl, driedover MgSO₄, and concentrated to give a clear oil. This crude oil waschromatographed on silica gel using 30% EtOAc in hexane as eluent togive the acylated intermediate 152 (138 mg) as a clear glass. The BOCgroup was removed from this intermediate as described in the referenceabove to give the title amine 153.Preparation of the Aniline of Animycin A₃ (154).

To a stirred solution of Antimycin A₃ (25 mg, 0.048 mmol) in 2.5 mL ofCH₂Cl₂ cooled to 0° C., was added pyridine (11 μL) and PCl₅ (27 mg, 0.13mmol). The mixture was refluxed for 1.5 hours, then was cooled to −30°C., and methanol (2.5 mL) was added, and the mixture was allowed to warmto room temperature and stirred overnight. The solution was poured intoa 0° C. mixture of 13 mL CH₂Cl₂ and 13 mL of saturated sodiumbicarbonate. The mixture was shaken in a separatory funnel and thelayers were separated. The aqueous layer was extracted with CH₂Cl₂ (2×5mL) and the combined organic layers were dried (MgSO₄), filtered andconcentrated to afford the aniline of Antimycin A₃.

General Procedures for Coupling of Amines withOrtho-hydroxyheteroaromatic Carboxylic Acids to Generate theHeterocyclic Aromatic Amides 2.

Coupling Procedure A: Preparation ofN-(2-(4-Chlorophenyl)ethyl)-3-hydroxypyridine-2-carboxamide (233).

A stirred mixture of 3-hydroxypyridine-2-carboxylic acid (1.39 g, 0.01mol) in dry THF (60 mL) under argon was cooled to −20° C. To this wasadded all at once a 20% solution of phosgene in toluene (5.1 g, 0.01mol) and the resulting mixture was stirred for 90 minutes while thetemperature slowly rose to 0° C. The reaction mixture was then recooledto −20° C. and a solution of diisopropylethylamine (2.58 g, 0.02 mol) inTHF (20 mL) was added dropwise over 30 minutes. After the addition wascomplete, the mixture was stirred an additional 2 hours as thetemperature was slowly brought to 0° C. Stirring was continued at 0° C.overnight. To this stirred mixture was added, all at once,2-(4-chlorophenyl)ethylamine (1.56 g, 0.01 mol), and the resultingmixture was stirred at room temperature for 6 hours. The mixture wasdiluted with ether (100 mL), washed with 1N HCl (100 mL), dried (MgSO₄)and concentrated to give the title compound as an off-white solid (1.95g). The mass spectrum showed the expected 3:1 parent ion ratio at m/e276 and 278.Coupling Procedure B: Preparation of3-Hydroxy-4-methoxy-N-(4-(4-trifluoromethylphenoxy)phenyl)-pyridine-2-carboxamide(425).

To a stirred solution of 4-(4-trifluoromethylphenoxy)aniline (0.20 g,0.8 mmol) and DMAP (0.10 g, 0.085 mmol) in CH₂Cl₂ (10 mL) was added allat once a solution of3-benzyloxy-6-bromo-4-methoxypyridin-2-carbonylchloride (3) (0.29 g, 0.8mmol) in CH₂Cl₂ (5 mL). The resulting mixture was stirred overnight atroom temperature then poured into 2N HCl (10 mL). The organic layer wasseparated and the aqueous layer extracted with CH₂Cl₂ (2×10 mL). Theorganic layers were combined, dried (MgSO₄) and concentrated to give agummy solid. This solid was taken up in EtOAc (20 mL), and triethylamine(0.80 g, 0.8 mmol) and 5% Pd on carbon (0.10 g) were added. Theresulting mixture was subjected to a hydrogen atmosphere (initialpressure=50 psi) on a Parr shaker for 30 minutes. The mixture wasfiltered, washed with 0.1N HCl (20 mL), dried (MgSO₄) and concentratedto give the title compound as an off-white solid (0.14 g), m.p.=122-129°C.Coupling Procedure C: Preparation ofN-(4-Cyclohexylphenyl)-3-hydroxypyridine-2-carboxamide.

To a stirred solution of 3-hydroxypyridine-2-carboxylic acid (obtainedfrom 16 by catalytic hydrogenation in the presence of Pd/C as describedearlier) (0.42 g, 3 mmol) and 4-cyclohexylaniline (0.35 g, 2 mmol) indry DMF (5 mL) were successively added 1-hydroxybenzotriazole (0.48 g),EDCI (0.65 g) and N-methylmorpholine (1.41 g). An additional amount ofDMF (5 mL) was added and the reaction mixture stirred at roomtemperature overnight. The mixture was poured into water (200 mL), thenextracted with EtOAc (2×75 mL). The organic extracts were combined,washed with water (100 mL), and saturated NaCl solution (50 mL), dried(MgSO₄) and concentrated. The crude oil which solidified upon standingwas chromatographed on silica gel (4:1 petroleum ether-EtOAc) to givethe title compound (0.42 g) as a tan solid, m.p. 91-93° C.

Modification of Heterocyclic Aromatic Amides to Other HeterocyclicAromatic Amides

Preparation of4-Hydroxythiophene-N-(3,3,5,5-tetramethylcyclohexyl)-3-carboxamide(554).

4-Methoxythiophenecarboxylic acid and 3,3,5,5-tetramethylcyclohexylaminewere coupled together following general coupling procedure C describedearlier, to give4-methoxythiophene-N-(3,3,5,5-tetramethylcyclohexyl)-3-carboxamide.

A solution of 500 mg of this methoxythiopheneamide in 15 mL ofchloroform under a drying tube was stirred in a Dry Ice-acetone bath for5 minutes. To this solution was added dropwise over 15 minutes asolution of 940 mg of boron tribromide (2 equivalents) in 10 mL ofchloroform. Stirring was continued while the reaction mixture warmed toroom temperature, and then overnight. The reaction mixture was thenplaced in a cold water bath, and 15 mL of water was added dropwise.After stirring 15 minutes, the mixture was diluted with 50 mL of CH₂Cl₂and the organic layer separated. The water layer was washed with 50 mLof CH₂Cl₂. The combined organic extracts were washed with 25 mL of waterand saturated salt solution and dried. The extract was filtered andconcentrated. The residue was chromatographed on silica gel usingCH₂Cl₂-5% EtOAc as eluent, to give 310 mg of the title compound as tancrystals, m.p. 170-174° C. A sample was recrystallized from petroleumether-EtOAc to yield tan needles, m.p. 171-173° C.

Preparation of Coupled Intermediates 156a-d.

These intermediates were prepared as depicted in Scheme 42.

To a stirred solution of the isopropyl ester of (±)-serine hydrochloride(2.75 g) and triethylamine (3.55 g) in CH₂Cl₂ (75 mL) was added over afive minute period a solution of3-benzyloxy-6-bromo-4-methoxypyridin-2-carbonylchloride (3) (5.32 g) inCH₂Cl₂ (15 mL). The mixture was stirred for 30 minutes at roomtemperature, then poured into 1N HCl (75 mL). The organic layer wasseparated, washed with water (25 mL), dried (Na₂SO₄) and the solventevaporated to give a yellow gum (6.7 g). This material could berecrystallized from ether/hexane to give 155a as a white solid, m.p.100-103° C. A similar procedure starting from the methyl ester of(±)-serine hydrochloride afforded the methyl ester intermediate 155b.

To a stirred solution of 155a (1.17 g) triethylamine (0.31 g), and DMAP(0.06 g) in CH₂Cl₂ (25 mL) was added in one portionα-methylhydrocinnamoyl chloride (0.46 g). The resulting mixture wasstirred for 4 hours at room temperature, then poured into 2N HCl (15mL). The organic phase was separated, washed with 1N NaOH (15 mL), dried(MgSO₄) and the solvent evaporated to give 156a as a yellow oil (1.45g). The NMR (CDCl₃) was consistent with this oil being a 1:1 mixture ofdiastereomers.

A solution of 3-(t-butyldimethylsilyloxy)butyryl chloride (3.55 g)(prepared from the corresponding t-butyldimethylsilyl ester by themethod of A. Wissner and C. V. Grudzinskas, J. Org. Chem., 1978, 43,3972), in CH₂Cl₂ (10 mL) was added rapidly to a cold (0° C.), stirredsolution of 155b (6.6 g) and DMAP (0.18 g) in dry pyridine (25 mL). Thereaction mixture was stirred for 15 minutes at 0° C. then at roomtemperature for three hours. After dilution with ether (200 mL), themixture was extracted with water (2×100 mL), dried (MgSO₄) and thesolvent evaporated. Toluene (25 mL) was added to the residue and againthe solvent evaporated. The yellow oily residue was purified viachromatography (silica gel, 7:3 hexane/acetone) to give 156b as amixture of diastereomers.

To a stirred solution of 2-benzyl-3-(t-butyldimethylsilyloxy)propionicacid (7.36 g) (N. P. Peet, N. L. Lentz, M. W. Dudley, A. M. L. Ogden, D.E. McCarty, and M. M. Racke, J. Med. Chem., 1993, 36, 4015), in DMF (20mL) was added all at once t-butyldimethylsilyl chloride (4.52 g), thenimidazole (4.1 g), and the resulting mixture stirred at room temperaturefor 24 hours. The mixture was diluted with water (300 mL) then extractedwith pentane (3×100 mL). The pentane phase was washed with water, dried(Na₂SO₄), and the solvent evaporated to give a colorless oil (9.5 g).The NMR (CDCl₃) was consistent with this being a mixture ofdiastereomers. This ester (4.1 g) was converted to the correspondingacid chloride by the method of N. P. Peete, et al., J. Org. Chem., 1978,43, 3972. This acid chloride was condensed with 155b (4.4 g) asdescribed above to give after silica gel chromatography (4:1hexane/acetone) the desired 156c as a mixture of diastereomers.

To a stirred solution of 156c (4.5 g) in methanol (35 mL) was addedconc. HCl (1.5 mL). The resulting mixture was stirred at roomtemperature for 30 minutes, diluted with water (200 mL), then extractedwith CH₂Cl₂ (2×100 mL). The organic phase was dried (MgSO₄), and thesolvent evaporated. The residue was purified via silica gelchromatography (7:3 hexane/acetone) to give 156d as a pale yellow gum(2.8 g). The NMR (CDCl₃) showed it to be a mixture of diastereomers.

156a-d were converted to the corresponding deprotected heterocyclicaromatic amides by hydrogenation in the presence of Pd/C as describedearlier.

Preparation of Indermediate 158.

Synthesis of this intermediate is shown in Scheme 43. Amide 157 wasprepared from (+)-trans-1-Hydroxy-2-aminocyclopentane hydrobromide (7.09g, 38.9 mmol) and3-benzyloxy-6-bromo-4-methoxypyridin-2-carbonylchloride (3) (13.8 g,38.9 mmol) in CH₂Cl₂ (150 mL), following general coupling procedure B,and purified by flash chromatography using 1:1 hexanes-EtOAc as eluent.This gave 157 (13.4 g) as a white solid, m.p. 56-57° C.

Dimethylsufoxide (7.4 mL, 104.1 mmol) was added slowly to a −78° C.solution of oxalyl chloride (4.54 mL, 52.08 mmol) in CH₂Cl₂ (100 mL),followed by a solution of amide 157 (10.46 g, 24.8 mmol) in CH₂Cl₂ (25mL). After 30 min, Et₃N was added and the solution slowly warmed to roomtemperature. The mixture was poured into satd. NH₄Cl (100 mL) andextracted with CH₂Cl₂ (2×100 mL). The combined organic layers werewashed with brine, dried and the solvent evaporated. The residue waspurified via column chromatography, using 1:1 EtOAc-hexane as theeluent, to give the ketone 158 (9.64 g, 94%), pure by GC/MS and ¹H-NMR.

Both 157 and 158 were converted to the corresponding deprotectedheterocyclic aromatic amides by hydrogenation in the presence of Pd/C asdescribed earlier.

Preparation of Intermediates 160a-d.

These intermediates were prepared as depicted in Scheme 44. Coupling ofserinol with 3-benzyloxy-6-bromo-4-methoxypicolinic acid (16) followinggeneral coupling procedure C, afforded 1,3-diol 159 as a colorless oil,pure by ¹H, ¹³C-NMR and IR spectra.

1,3-diol 159 (1 mmol) was condensed with the appropriate carbonylcompound (2 mmol) or the corresponding dimethyl acetal (2 mmol) byrefluxing in benzene (20 mL/mmol) in the presence of a catalytic amountof p-toluenesulfonic acid (0.1 mmol) in a Dean-Stark setup.

Thus, condensation of 159 and 1,3,3-trimethoxypropane gave the acetal160a as a 2:1 mixture of syn and anti diastereomers. Mass spectrum (ES)indicated [M+] at (m/e) 495 and 497. ¹H-, ¹³C-NMR and IR spectra wereconsistent with the structure 160a.

Condensation of 159 and 2-methyl-3-(4-tert-butyl)phenylpropanone gavethe acetal 160b as a 3:1 mixture of syn and anti diastereomers. Massspectrum (ES) indicated [M+] at (m/e) 597. ¹H, ¹³C-NMR and IR spectrawere consistent with the structure 160b.

Condensation of 159 and dihydro-β-ionone gave the acetal 160c as a 2:1mixture of syn and anti diastereomers. Mass spectrum (EI) indicated [M+]at (m/e) 587. ¹H, ¹³C-NMR and IR spectra were consistent with thestructure 160c.

Condensation of 159 and 3,3,5,5-tetramethylcyclohexanone gave the acetal160d, consistent by ¹H, ¹³C-NMR and IR spectra.

Intermediates 160a-d were converted to the corresponding deprotectedheterocyclic aromatic amides by hydrogenation in the presence of Pd/C asdescribed earlier.

Preparation of Compounds 280 and 281.

Scheme 45 describes the preparation of these compounds. Thus,2,3,6,6-tetramethyl-2-cycloheptenylamine was first coupled to2-hydroxy-3-methoxy-2-picolinic acid using standard coupling procedureC, to give intermediate 161. Dichlorination of compound 161 according tothe procedure of Tetrahedron Lett. 1991,32, 1831-1834, afforded thedichloro derivative 281. Standard m-CPBA oxidation of 161 in CH₂Cl₂ ledto the N-oxide-containing epoxy analog 162, which upon treatment with H₂(45 psi) and 10% Pd/C under standard catalytic hydrogenation conditionsformed compound 280.

Preparation of trans-4-Hydroxy-3,3,5,5-tetramethylpicolinamide (264).

This compound was prepared as shown in Scheme 46. To a stirred solutionof keto-picolinamide 266 (56 mg, 0.18 mmol) in 2 mL of methanol wasadded sodium borohydride (20 mg, 0.53 mmol). The reaction was stirredfor 5 hours and the methanol evaporated. The crude material was dilutedwith 5 mL water and extracted with EtOAc (3×5 mL). The organic layer waswashed with water (1×5 mL) and brine (1×5 mL). The solution was driedover MgSO₄, filtered and concentrated. NMR and GC anaylses wereconsistent with the title compound 264 with trans stereochemistry in 95%purity.

Preparation of Compound 341.

Preperaion of this compound is depicted in Scheme 47. The benzyl esterprecursor 139 (Scheme 38) (33 mg, 0.046 mmol) was dissolved in 10 mL ofEtOAc and 110 mg of Pearlman's catalyst was added. The mixture wasshaken in a Parr apparatus under 50 psi of hydrogen pressure for 12hours. The solution was then filtered and concentrated. The residue wasthen dissolved in a minimal amount of ether and petroleum ether wasadded until a precipitate formed. The solid was collected by filtrationand dried to give the title compound 341.Preparation ofN-(3-Hydroxy-4-methoxy-2-pyridylcarbonyl)-2-amino-2-deoxy-alpha-D-glucopyranose(334).

1,3,4,6-Tetra-O-acetyl-2-amino-2-deoxy-alpha-D-glucopyranose (151) and3-hydroxy-4-methoxypicolinic acid were coupled together using standardcoupling procedure C. To a solution of the resulting picolinamide (0.19g, 0.38 mmol) in 6 mL of methanol was added lithium hydroxidemonohydrate (0.92 mmol, 40 mg). The reaction mixture was stirred at roomtemperature overnight. The solution was neutralized by the addition ofDOWEX® 5×8-100 acidic resin (0.5 g). The mixture was filtered andconcentrated to afford the title compound (110 mg, 88%).

General Preparation of Exocylic Ester 166a, Carbamate 166b, andCarbonate 166c.

These compounds were generally prepared as depicted in Scheme 48,starting with amine 164, prepared according to the procedures of M.Shimano, et al., Tetrahedron, 1998, 54, 12745. This amine was coupledwith 3-benzyloxy-6-bromo-4-methoxypicolinic acid 16 following standardcoupling procedure C described earlier, then the resulting intermediate165 was reacted with the appropriate carboxylic acid chloride, alkylisocyanate, or alkyl chloroformate in the presence of base to afford thedesired protected ester 166a, carbamate 166b, or carbonates 166c,respectively. Deprotection of these compounds following the proceduresdescribed earlier using H₂ in the presence of Pd/C afforded the desiredester, carbamate, or carbonate. The above steps were used to prepareother analogous esters, carbamates, and carbonates.

Preparation of 166a.

To a stirred solution of 165 (180 mg, 0.29 mmol) in pyridine (10 mL) wasadded slowly cyclopropanecarbonyl chloride (0.45 mL, 5 mmol) over 5minutes. The mixture was allowed to stir under a N₂ atmosphere at roomtemperature overnight. The resulting mixture was poured into 1N HCl (30mL) and extracted with EtOAc (2×75 mL). The organic layers were combinedand washed with water (25 mL) then saturated NaCl (25 mL), dried overMgSO₄, and concentrated to give an orange oil. The crude oil waschromatographed on silica gel using a 30% to 50% EtOAc in hexanegradient as eluent to give the title compound 166a (100 mg) as a clearoil.

Preparation of 166b.

To a stirred solution of 165 (200 mg, 0.33 mmol) in CH₂Cl₂ (5 mL) wasadded triethylamine (2 drops), DMAP (1 mg), and isopropyl isocyanate(0.2 mL, 2 mmol). The resulting mixture was stirred under a nitrogenatmosphere at room temperature overnight. The reaction mixture waspoured into 1N HCl (25 mL) and extracted with EtOAc (2×50 mL). Theorganic layers were combined and washed with water then saturated NaCl,dried over MgSO₄, and concentrated to give a pink foam. The crude foamwas chromatographed on silica gel using a 30% to 50% EtOAc in hexanegradient as eluent to give the title compound 166b (90 mg) as a whitesolid.

Preparation of 166c.

A stirred solution of 165 (180 mg, 0.29 mmol) in pyridine (5 mL) andCH₂Cl₂ (5 mL) was cooled to 0° C. in an ice bath under a nitrogenatmosphere. Isopropyl chloroformate (1M in toluene, 5 mL) was slowlyadded to the cooled mixture over 1 minute. The ice bath was removed andthe mixture was stirred at room temperature overnight. The reactionmixture was partitioned between 1N HCl (25 mL) and EtOAc (75 mL). Theorganic layer was washed with water then saturated NaCl, dried overMgSO₄, and concentrated to give a clear oil. The crude oil waschromatographed on silica gel using a 30% to 50% EtOAc in hexanegradient as eluent to give the title compound 166c (80 mg) as a clearoil.

Preparation of Intermediates 167 and 168.

The diastereomeric mixture of amines 53 obtained as described earlier(Scheme 9) was coupled with acid chloride 3 via the general couplingprocedure A previously described (Scheme 49), to give a mixture ofdiastereomers 167 and 168. These were separated by careful silica gelchromatography (85:15 hexane/acetone) to give pure 167 and 168 each inabout 35% yield. These were deprotected with H₂ in the presence of Pd/Cas described earlier.

Table I illustrates additional compounds of Formula I made fromappropriate starting materials by the above described procedures.

Fungicide Utility

The compounds of the present invention have been found to control fungi,particularly plant pathogens and wood decaying fungi. When employed inthe treatment of plant fungal diseases, the compounds are applied to theplants in a disease inhibiting and phytologically acceptable amount.Application may be performed before and/or after the infection withfungi on plants. Application may also be made through treatment of seedsof plants, soil where plants grow, paddy fields for seedlings, or waterfor perfusion. Other application may be made via wood treatment tocontrol the destruction of wood and/or wood products.

As used herein, the term “disease inhibiting and phytologicallyacceptable amount”, refers to an amount of a compound of the presentinvention which kills or inhibits the plant pathogen and prevents,eradicates, or arrests plant disease for which control is desired, butis not significantly toxic to the plant. This amount will generally befrom about 1 to 1000 ppm, with 10 to 500 ppm being preferred. The exactconcentration of compound required varies with the fungal disease to becontrolled, the type of formulation employed, the method of application,the particular plant species, climate conditions, and other factors. Asuitable application rate is typically in the range from about 50 toabout 1000 grams per hectare (g/Ha).

The compounds of the invention may also be used to protect stored grainand other non-plant loci from fungal infestation.

The following experiments were performed in the laboratory to determinethe fungicidal efficacy of the compounds of the invention.

Biological Evaluation of Inhibition of in vitro Fungal Growth

Culture Conditions: Suspensions of fungal conidia or mycelial fragmentsare prepared in sterile potato dextrose broth (Difco) for Magnaporthegrisea (Pyricularia oryzae—PYRIOR), Rhizoctonia solani (RHIZSO),Mycosphaerella graminicola (Septoria tritici—SEPTTR), Stagonosporanodorum (Leptosphaeria nodorum—LEPTNO), Ustilago maydis (USTIMA), and inrye seed broth for Phytophthora infestans (PHYTIN). The suspensions arepipetted into sterile 96 well microtiter plates containing samples ofthe experimental fungicides dissolved in dimethylsulfoxide. Theconcentration of the fungicide varies from 0.001 to 100 ppm with thefinal solvent concentration not exceeding 1% of the medium. The fungiare allowed to grow for various time intervals at 24 to 30° C. until thewells become turbid from the growth of the fungi in control wellscontaining only the solvent. At that time growth inhibition isdetermined by visual inspection of each well and the percent inhibitionof growth as compared to the solvent treated controls is determined.

In Table II, a “+” indicates that the test material gave at least 80%growth inhibition and a “−” indicates less than 80% growth inhibition ofthe designated pathogen when incorporated into the growth medium at aconcentration of 25 ppm. A blank space indicates not tested.

Biological Evaluation of Control of in vivo Whole Plant Fungal Infection

Compound formulation was accomplished by dissolving technical materialsin acetone, with serial dilutions then made in acetone to obtain desiredconcentrations. Final treatment volumes were obtained by adding 9volumes 0.05% aqueous Tween-20 or 0.01% Triton X-100, depending upon thepathogen.

Downy Mildew of Grape (Plasmopara viticola—PLASVI) (24 Hour Protectant):Vines (cultivar Carignane) were grown from seed in a soilless peat-basedpotting mixture (“Metromix”) until the seedlings were 10-20 cm tall.These plants were then sprayed to run-off with the test compound at arate of 100 ppm. After 24 hours the test plants were inoculated byspraying with an aqueous sporangia suspension of Plasmopara viticola,and kept in a dew chamber overnight. The plants were then transferred tothe greenhouse until disease developed on the untreated control plants.

Late Blight of Tomato (Phytophthora infestans—PHYTIN) (24 HourProtectant): Tomatoes (cultivar Rutgers) were grown from seed in asoilless peat-based potting mixture (“Metromix”) until the seedlingswere 10-20 cm tall. These plants were then sprayed to run-off with thetest compound at a rate of 100 ppm. After 24 hours the test plants wereinoculated by spraying with an aqueous sporangia suspension ofPhytophthora infestans, and kept in a dew chamber overnight. The plantswere then transferred to the greenhouse until disease developed on theuntreated control plants.

Brown Rust of Wheat (Puccinia recondita—PUCCRT) (24 Hour Protectant):Wheat (cultivar Yuma) was grown in a soilless peat-based potting mixture(“Metromix”) until the seedlings were 10-20 cm tall. These plants werethen sprayed to run-off with the test compound at a rate of 100 ppm.After 24 hours the test plants were inoculated by spraying with anaqueous spore suspension of Puccinia recondita, and kept in a dewchamber overnight. The plants were then transferred to the greenhouseuntil disease developed on the untreated control plants.

Powdery Mildew of Wheat (Erysiphe graminis—ERYSGT) (24 Hour Protectant):Wheat (cultivar Monon) was grown in a soilless peat-based pottingmixture (“Metromix”) until the seedlings were 10-20 cm tall. Theseplants were then sprayed to run-off with the test compound at a rate of100 ppm. After 24 hours the test plants were inoculated by dusting withconidia from powdery mildew infected wheat plants. The plants were thentransferred to the greenhouse until disease developed on the untreatedcontrol plants.

Leaf Blotch of Wheat (Septoria tritici—SEPTTR) (24 Hour Protectant):Wheat (cultivar Yuma) was grown in a soilless peat-based potting mixture(“Metromix”) until the seedlings were 10-20 cm tall. These plants werethen sprayed to run-off with the test compound at a rate of 100 ppm.After 24 hours the test plants were inoculated by spraying with anaqueous spore suspension of Septoria tritici, and kept in a dew chamberovernight. The plants were then transferred to the greenhouse untildisease developed on the untreated control plants.

Glume Blotch of Wheat (Leptosphaeria nodorum—LEPTNO) (24 HourProtectant): Wheat (cultivar Yuma) was grown in a soilless peat-basedpotting mixture (“Metromix”) until the seedlings were 10-20 cm tall.These plants were then sprayed to run-off with the test compound at arate of 100 ppm. After 24 hours the test plants were inoculated byspraying with an aqueous spore suspension of Leptosphaeria nodorum, andkept in a dew chamber overnight. The plants were then transferred to thegreenhouse until disease developed on the untreated control plants.

In Table II, a “++” indicates that the test material gave at least75-100% control of fungal infection when compared to disease incidenceon untreated plants, a “+” indicates that the test material gave 25-74%control of fungal infection, and a “−” indicates <25% control of fungalinfection of the designated pathogen at a concentration of 100 ppm. Ablank space indicates not tested.

Compound Molecular Melting Number Molecular Structure Appearance Ion (M)Point (°C.) 201

Yellow oil 264 202

Pale yellow oil 234 203

Pale yellow solid 63-64 204

White solid 302 205

White solid 290 206

Oily white solid 272 207

Yellow oil 286 208

Colorless thin needles 112-115 209

Colorless crystals 123-126 210

Colorless crystals 139-142 211

Colorless crystals 154-157 212

White solid 131-132 213

Tan solid 248,250 214

Yellow solid 282 215

Orange-white solid 242 216

Off-white solid 127-129 217

Tan solid 131-133 218

Off-white solid 97-99 219

Off-white solid 65-67 220

Off-white solid 95-97 221

White solid 100-101 222

Pale yellow oil 242 223

White solid 83-84 224

White solid 75-76 225

White solid 41-43 226

White solid 96-97 227

White solid 78-79 228

White solid 106-109 229

White solid 89-91 230

Yellow oil 231

Orange oil 292 232

Orange oil 292 233

Off-white solid 276,278 234

Yellow oil 270 235

Brown solid 221 236

Colorless crystals 42-45 237

Colorless solid 122-134 238

Colorless needles 105-107 239

Off-white fluffy crystals 254,256 240

Yellow fluffy crystals 282 241

Tan solid 304 242

Gold syrup 304 243

Brown powder 287 244

Yellow gum 436 245

Colorless oil 246

Off-white solid 140-142 247

Pale yellow solid 340 248

Yellow oil M + 1 253 249

Thick yellow oil 250 250

Off-white solid 104-106 251

Amber oil 252

Yellow gel 253

Clear gel 254

Yellow gel 255

White powder 340 256

White solid 257

Oil 433 258

Gum M + 1 345 259

Gum M + 1 341 260

White solid 396 147-149 261

Pale yellow oil M + 1 421 262

White solid M + 1 454 59-60 263

Off-white foam M + 1 454 264

White solid 322 265

Yellow oil 266

White solid 362 267

White foam 268

White solid 426 175-200 269

White solid 461 55-56 270

Off-white solid 168-172 (Dec) 271

Off-white solid 181-183 (Dec) 272

Off-white solid 535 273

White solid 297 113-115 274

White solid 427 275

Yellow gel 358 276

Colorless gel 438 277

Gum 306 278

Pale yellow oil 302 279

Gum 318 280

White foam 334 281

White foam M−1 388 282

Pale yellow oil 278 283

Clear oil 284

Solid 122-128 285

Tan solid 174-179 286

Thick colorless oil 384 287

White solid 262 288

Pale yellow solid 304 289

Pale yellow gum 384 290

White solid 310 291

Dark brown oil 316 292

Pasty yellow solid 344 293

White solid 143-460 (Dec) 294

Yellow gum 450 295

Colorless gum 450 296

Colorless gum 450 297

Yellow gum 450 298

Yellow gum 348 299

Pale yellow gum 439 300

White solid 439 301

Colorless gum 510 302

White solid 304 303

White foamy solid 401 304

Brown glass 294, 296 305

White solid 145-147 306

White solid 356 150-152 307

White solid 168-170 308

Amber glass 356 309

Sticky oil 384 310

Glass 252 311

White solid 356 156-158 312

Oil 370 313

Oil 370 314

Light brown gum 296 315

White solid 379 316

White solid M + 1 429 317

428 318

Gum 418 319

White solid 418 139-140 320

White solid 108.5- 109.5 321

Yellow glass 412 322

Yellow sticky solid 400 323

Yellow sticky solid 394 324

White solid 345 141-143 325

Glass 398 326

Clear gel 327

Clear gel 328

Off white solid 329

White solid 330

White solid 331

White solid 332

White solid 333

White solid 334

Yellow solid 335

White solid 336

White solid 337

White solid M + 1 423 338

Tan oily solid M + 1 437 339

White waxy solid M + 1 513 340

Tacky solid 270 341

Brown oil 342

Clear oil 343

Pale yellow gum M + 1 403 344

Pale yellow gum M + 1 403 345

Amber gum M + 1 417 346

Pale yellow oil M + 1 419 347

Pinkish gum M + 1 427 348

Pinkish gum M + 1 469 349

Pale yellow gum M + 1 503 350

Amber gum M + 1 447 351

Pale yellow gum M + 1 445 352

Amber gum 454 353

Yellow gum 516 354

Yellow gum M + 1 499 355

Yellow gum M + 1 545 356

Pale yellow gum M + 1 579 357

Yellow gum M+ 1 589 358

Pale yellow gum 516 359

Pale yellow gum 516 360

Yellow gum 472 361

Yellow oil 362

Yellow oil M + 1 489 363

Yellow oil M + 1 486 364

Yellow oil M + 1 503 365

Yellow oil 366

Yellow oil 367

Yellow Oil 368

Yellow oil M + 1 435 369

Yellow oil 370

Yellow oil M + 1 387 371

Yellow oil M + 1 373 372

Yellow oil 373

Yellow oil 374

Yellow oil M + 1 423 375

White solid 400 376

Pale yellow solid 473 190-192 377

White solid M + 1 379 234-235 378

Solid 338 379

Pale yellow solid 439 118-121 380

White solid 406 107-108 381

White solid 382

White solid 383

White solid 444 384

White solid 172-174 385

Ivory solid 194-196 386

Clear oil 512 387

Off-white foam 512 388

White solid 212-214 389

Off-white foam 390

Yellow solid 391

Tan foam 540 392

Clear oil 393

Yellow glass 394

Pale yellow solid 181-185 395

Yellow solid 562 396

White foam M + 1 595 397

Yellow solid 398

White solid 399

White foam M + 1 530 400

White solid 401

White gummy solid 530 402

Off-white solid 182-184 403

White solid 194-195 404

White solid 126-127 405

Pale yellow solid 416 406

Off-white solid 416 407

Off-white solid 431 408

White solid M + 1 446 409

White solid 445 410

Yellow solid 204-205 411

Off-white solid 350 412

Off-white solid 350 413

Off-white solid 350 414

Off-white solid 350 415

Off-white solid 350 416

Off-white solid 350 417

Off-white solid 350 418

Off-white solid 361 419

Off-white solid 361 420

Off-white solid 361 421

Off-white solid 361 422

Off-white solid 361 423

Pale yellow solid 424

Off-white solid 404 425

Off-white solid 404 426

White solid 125-127 427

White solid 145-147 428

Off-white solid 366 429

Off-white solid 366 430

Off-white solid 366 431

Off-white solid 366 432

Off-white solid 366 433

Off-white solid 366 434

Off-white solid 366 435

Off-white solid 366 436

White solid 370,372 109-110.5 437

Off-white solid 370,372 438

Off-white solid 370,372 439

Off-white solid 370,372 440

Off-white solid 370,372 441

Off-white solid 370,372 442

Off-white solid 370,372 443

Off-white solid 370,372 444

White solid 133-134 445

Yellow solid 167-169 446

White solid 420 447

White solid 418 448

White solid 418 449

Off-white solid 431 450

White solid >260 451

Off-white solid M + 1 433 196 (Dec) 452

Off-white solid 432 453

Yellow solid 240-242 454

Off-white solid 240-242 455

White solid 358 456

White solid 392 457

Off-white solid 460 458

Off-white solid 141-142 459

Off-white solid 161-163 460

White solid 149-153 461

White solid 169-171 462

White solid 141-143 463

White solid 140-141.5 464

White solid 179-181 465

White solid 160-162 466

White solid 198-200 467

Pale yellow solid 198-201 468

White solid 430 469

White solid 149-151 470

White solid 173-175 471

White solid 193-195 472

White solid M + 1 406 473

Yellow solid 812 474

Colorless crystals 107-110 475

Yellow solid 168-172 476

Tan crystals 118-121 477

Yellow gum 322 478

Light yellow solid 184-187 479

Light yellow solid 129-132 480

Gummy tan solid 310,312 481

Glass 514 482

White solid 483

Solid 124-126 484

White solid 485

Yellow solid 140-142 486

Off-white solid 111-113 487

White solid 488

White solid 489

Yellow gum 490

Light-yellow Oil 412,414 491

Yellow gum 396,398 492

White solid 452,454 493

White solid 452,454 494

White solid 452,454 495

Orange gum 452,454 496

White solid 452,454 497

Orange whitesolid 452,454 498

White Solid 452,454 499

White Solid 452,454 500

White Solid 409,411 501

White foam M − 2 631 502

Off-white salid 232-235 (Dec) 503

White solid 213-215 (Dec) 504

Grey solid 70-78 505

Dark tar 506

Dark tar 507

Dark tar 508

Dark tar 272 509

Dark tar 276, 278 510

Dark tar 310 511

Dark tar 326 512

Dark tar 513

Tan glass 485 514

White solid 180-181 515

Light-tan solid 190-192 516

Off-white crystals 193-194 517

White crystals 229-230 518

White solid 219-221 519

Tannish-white solid 190-192 520

Light-yellow needles 234-235 521

Light-tan crystals 200-201 522

White crystals 223-224 523

White solid 188-190 (Dec) 524

Colorless needles 307-308 525

Colorless crystals 247-250 526

Grey solid 320-327 527

Grey solid 120-130 528

Colorless needles 286-288 529

Colorless solid 512 530

Colorless crystals 329-331 531

Colorless solid 103-108 532

White solid 233 (Dec) 533

Bright yellow plates 248-250 (Dec) 534

Yellow solid M − 1 484 535

Yellow solid 239-243 (Dec) 536

Off-white solid 80-83 537

Tan solid 84-86 538

Beige solid 108-110 539

White solid 263-265 540

White solid 195 (Dec) 541

White crystalline solid >300 542

Clear solid 220 (Dec) 543

Tan solid 283-285 544

Colorless glass M + 1 503 M− 1 501 545

Colorless solid 265-268 546

Yellow crystals 208-213 547

Yellow-brown solid M + 1 533 548

Yellow solid 261-265 549

Colorles needles 121-125 550

Colorless glass M + 1 491 551

Yellow solid 380 552

Yellow solid 96-102 553

Glassy solid M + 1 492 554

Tan crystals 170-174 555

Brown gum 379 556

White solid 195 (Dec) 557

White solid 205-208 558

White solid 199-205 559

White solid 215-217 560

Light brown solid 186-188 561

Brown glassy solid 115-117 562

Off-white solid 163-165 563

Yellow solid >300

ERYSGT in LEPTNO in PHYTIN in PLASVI in PUCCRT in SEPTTR in Compoundvivo 1 Day vivo 1 Day vivo 1 Day vivo 1 Day vivo 1 Day vivo 1 Day NumberProtectant Protectant Protectant Protectant Protectant Protectant 201 −− − − − − 202 − − − − − − 203 204 − − − − − + 205 − − − + − − 206 − − −− − − 207 − − − − − − 208 − − + − + − 209 − − − − − + 210 − − − − − +211 − + − − − + 212 − − − + − − 213 − − + + ++ − 214 − − − + − − 215 − −− − − − 216 − − − − − − 217 + − − − − − 218 − − − + − − 219 − − − + − −220 − − + + − − 221 − − − − − − 222 − − − − + − 223 − − − + − − 224 − −− − − − 225 − − − − − − 226 + − − − − − 227 − − − − − − 228 − − + − − −229 − − − − − − 230 − + − − − + 231 − − − + − − 232 + − − − − − 233 − −− + − + 234 − − − + − + 235 − − − − − − 236 − − − − − − 237 − + − − ++ +238 − + − − − − 239 − + − + + + 240 − + − ++ − ++ 241 − + − + + + 242 −− − − − + 243 − + − − + + 244 − + − − − 245 − + − + − + 246 + ++ − − − +247 − + − + − + 248 − + − − − − 249 − + − − − + 250 − + + − + − 251 −++ + + ++ ++ 252 − + + − + + 253 − + − − + + 254 − + − − + + 255 − ++ −− + + 256 + + − − + + 257 − ++ − + + + 258 − + − − − + 259 − + + + + +260 − + − + − + 261 − + + + + + 262 − + − + − + 263 − + − − − − 264 − −− − + + 265 + + − + − + 266 − + − − − + 267 − + − ++ + − 268 − + −++ + + 269 − − − ++ + + 270 + ++ + + + + 271 − + + + − + 272 − + − − −++ 273 − + − + − + 274 − ++ − + ++ + 275 − + − − − + 276 − ++ − + + +277 − + − − − ++ 278 − + − + + + 279 + + + − − + 280 − + + + + +281 + + + ++ + + 282 − + − − + + 283 − + − − + ++ 284 − + − − + + 285− + − − − + 286 − + − + − 287 − + − + + + 288 − + − + − + 289 + + − ++ +++ 290 + ++ − ++ ++ + 291 − + − − − 292 − ++ − − + 293 − + − − − + 294 −++ − + − 295 − + − + + ++ 296 − + − − − 297 − + − + − + 298 − + − + + +299 − + − ++ + 300 − + − ++ − 301 − + − − + 302 − + − + − + 303 − + + ++− + 304 − + − + − ++ 305 − − ++ − − − 306 − − − + − + 307 + − − − −308 + − − + − + 309 + + − − − − 310 + − − + − − 311 − + − + ++ 312 + + −− − + 313 + + − − + + 314 − + − + − − 315 − + − − − − 316 − + − + ++ −317 − − + + ++ − 318 − + + + + + 319 + − − + ++ + 320 − + − − − + 321 −− − − + − 322 + + − − + + 323 − ++ − − + ++ 324 + ++ − + + + 325 − + − +− − 326 − + − − − ++ 327 − + + − − ++ 328 − + − + − + 329 − + − − + +330 − − − + − − 331 − + − − − − 332 − + − − − + 333 − + − − + + 334 − +− − − − 335 − + + − − − 336 − + − − − + 337 − ++ − − + − 338 − ++ − −++ + 339 − ++ − − ++ ++ 340 + + − − − − 341 − − − − − + 342 + + − − ++ +343 + + − − − − 344 − + − − − + 345 − − − + + − 346 − − − + + + 347 − +− − + − 348 − + − − + + 349 − − − + ++ − 350 − ++ − − ++ − 351 − + − +++ − 352 − − − + + − 353 − − − + ++ − 354 + − − − ++ − 355 − − − + + −356 − + − + + + 357 − + − + ++ − 358 − + − − + + 359 − + − + ++ ++ 360 −++ − + + + 361 − + − + ++ − 362 363 364 365 366 367 368 369 370 371 372373 374 375 − + − + − + 376 + + − + − + 377 − + − − − − 378 − + − − − −379 + + − + + + 380 + + − + − − 381 − − − − + − 382 − ++ + + 383 − −− + + − 384 ++ ++ − − + + 385 − ++ + − + + 386 + ++ − ++ + + 387 + ++ −− + + 388 − ++ − − + + 389 − ++ − − + + 390 − ++ − − + + 391 − ++ −− + + 392 + ++ − − + + 393 − + − − + + 394 − ++ − − + + 395 − + − − + +396 − + − − + + 397 − + − − + + 398 − − − − + − 399 − ++ − − + + 400 +++ − + + + 401 − ++ − − + + 402 ++ ++ − + + + 403 − ++ − − + + 404 + +− + + + 405 − + − − − − 406 + + − − − + 407 − + − − − + 408 + + − + − +409 + ++ + − + + 410 − + − − − − 411 − − − − − − 412 − − − − + − 413 −− + + + − 414 − − + − + − 415 + − − − + − 416 − − − − + − 417 − ++ − − −− 418 − − − − + − 419 − − + − − − 420 − + − − − − 421 − + − − − − 422 −− + − − − 423 − + − − + + 424 + + + + + + 425 − − + − + + 426 +− + + + + 427 − + − + + + 428 − − − − − − 429 − − − − − − 430 − − + − −− 431 − − − − − + 432 − + − − + − 433 − − − − − − 434 + + − − − − 435− + − − − − 436 − + − − − + 437 − − + − − − 438 − − − − − − 439 − + −− + − 440 − ++ − − + + 441 − − − − − − 442 − − + − + − 443 − − − + + −444 − + − + + + 445 + ++ − − + + 446 − − + − − − 447 − + − + − − 448 −++ − − + + 449 − + − − − + 450 − + − − − + 451 − + − − + − 452 − + − −− + 453 − + − − − + 454 − + − − − + 455 − + − + − + 456 − − − + − + 457− − − − − + 458 − ++ − − + − 459 + ++ − − + + 460 + + − + + 461 − + −− + + 462 − + − − + + 463 − − − − − + 464 − + − − − + 465 − + − − − +466 − + − − − + 467 + + − − − + 468 − − − − − + 469 − + − − ++ + 470 + +− + + 471 − + − − + + 472 − + − − + + 473 − ++ − − + + 474 − + − − + −475 − ++ − − + 476 − + − − − − 477 − + − − − + 478 − + − + + + 479 − + −− − + 480 − + − − − − 481 − + − − − + 482 − + − − − + 483 − − − − − −484 − − − − − − 485 − − − + − − 486 − − − − − − 487 − − − − + − 488 − −− + + + 489 − − − − + − 490 − − − + + + 491 − − − + − − 492 − − − − − +493 − − − − − + 494 − − − − − + 495 + − − − + + 496 − − − − + + 497 − +− − + + 498 − − − − + + 499 − + − + + − 500 − − − − − + 501 − + − − + −502 − + − + + + 503 + + − + + − 504 − + − − − − 505 − − − + − − 506 − −− + − − 507 − − − + − − 508 − − − + − − 509 − − − + − − 510 − − + − − −511 − − − + − − 512 − − + + − − 513 − ++ − + + − 514 − + − − − − 515 − −− + − + 516 − − − + − − 517 − + − + − − 518 − − + + − − 519 − + − − − −520 − + − − − − 521 − + + − − − 522 − ++ − − − − 523 + ++ + + + + 524 −− − − − + 525 − ++ − − + + 526 − + − − − + 527 − − − + + + 528 − − − −− + 529 − + − − + + 530 − + − − + + 531 + + − − − + 532 + + + + + + 533− + + + + + 534 − ++ − ++ + + 535 − + − + + + 536 − ++ − − + + 537 − ++− + + + 538 − + − + + + 539 − + − − + + 540 − − − − − + 541 − − − − − +542 − − − − − + 543 − + − − − − 544 − + − − + + 545 − + + + + + 546 − +− + + + 547 − − + + + + 548 − + + + − + 549 − + − + − + 550 + ++ −++ + + 551 + + − − − + 552 + − + ++ − − 553 + ++ ++ ++ + + 554 − + −− + + 555 − + − − − + 556 − + − − + − 557 − + − ++ + + 558 − + − ++ + +559 − + − − + − 560 − + − + + + 561 + − − + + + 562 + − − − − + 563 − +− − − − LEPTNO in PHYTIN in PYRIOR in RHIZSO in SEPTTR in USTIMA invitro vitro vitro vitro vitro vitro Compound Growth Growth Growth GrowthGrowth Growth Number Inhibition Inhibition Inhibition InhibitionInhibition Inhibition 201 − − + − − − 202 − + + − − − 203 + − + + + −204 − − − − − − 205 − − − − − − 206 + − + + + − 207 + − + − + − 208 − −− − − − 209 − − − − − − 210 − − − − − − 211 − − − − − − 212 − − + − − −213 − + − − + − 214 − − − − − − 215 − − − − + − 216 − − + − − − 217 − −− − − − 218 + + + + − + 219 + + + + + + 220 + + + + + + 221 − + + − + −222 − − − − − − 223 + + + − − + 224 − − + − − − 225 − + − − − − 226 − +− − − − 227 − + − − − − 228 − − − − − − 229 − − + − + − 230 + + + − + −231 − − + − − − 232 − − + − + − 233 + + + − + + 234 + + + − − −235 + + + + + + 236 + − − − − − 237 − − − − − − 238 − − − − − − 239 − −− − − − 240 − − − − − − 241 − + − + − − 242 + + + + + + 243 − − − − − −244 + − + − + − 245 − − − − − − 246 − − − − − − 247 + − − − + − 248 − −− − − − 249 − − − − − − 250 + + − − − − 251 + + − − + − 252 + + + + + −253 + + + − + − 254 + + + − + − 255 − − − − + − 256 − − − − − − 257 + +− − + + 258 + + − − + − 259 − − − − − − 260 + − − − − − 261 + + − − + −262 − − − − − − 263 − − − − − − 264 − − − − − − 265 − − − − − − 266 − −− − − − 267 + + − − − + 268 + + − − − − 269 − − − − − − 270 + − + + + +271 + + + + + + 272 − − − − + − 273 − − − − − − 274 + + + + + − 275 + −− + + − 276 + − − − − − 277 + − − − + − 278 − − − − − − 279 + + − − + −280 − − − − − − 281 − + + − − − 282 − − − − − − 283 − − − − − − 284 − −− − − − 285 − − − + − − 286 + − − + − − 287 − − − + − − 288 − − − + − −289 − − + + + − 290 + − + + + − 291 + − − + − − 292 + − − − − − 293 − −− − − − 294 + − + + + − 295 + − + + + − 296 + − + + − − 297 + − + + + −298 − − − + − − 299 + − − + − − 300 + − − + − − 301 + − + + − − 302 − −− − − − 303 − − − − − − 304 − − − + − − 305 − − − − − − 306 − − − − − −307 − − − − − − 308 − 309 − − − − − − 310 − − − − − − 311 − − − − − −312 − − − − − − 313 − − − − − − 314 − − − − − − 315 − − − − − − 316 +− + − − + 317 − − − − − − 318 + + − + + − 319 − − − − − − 320 − − − − −− 321 − − − − − − 322 + − − + − − 323 + − + + + − 324 + + − + + + 325 −− − − − − 326 − − − − − − 327 − − − − − − 328 − + − − − − 329 − − − − −− 330 − − − − − − 331 − − + − − − 332 − − − − − − 333 − − − − − − 334 −− − − − − 335 − − − − − − 336 − − − − − − 337 − − − − − − 338 − − − −− + 339 − − − − − − 340 − − − − − − 341 − − − − − − 342 − − − − − + 343− − − − − − 344 + − − − − − 345 − − − − − − 346 − + − − − − 347 − − − −− − 348 − − − − − − 349 − − − − − − 350 − − − − − − 351 − − − − − + 352− − − − − − 353 − − − − − − 354 − − − − − − 355 − − − − − − 356 − − − −− − 357 − − − − − − 358 − − − − − − 359 − − − − − − 360 − − − − − − 361− + + − + − 362 − − + − − − 363 − − + − − − 364 − − + − − − 365 − − + −− − 366 − + − − − − 367 − − + − − − 368 − − − + − − 369 − − − + − −370 + − − − − − 371 − − − + − − 372 − − − + − − 373 − − − + − − 374 + −− − − − 375 − − − − − − 376 − − − − − − 377 − + − − − − 378 − − − − − −379 − − − − − − 380 − − − − − − 381 + − − − + − 382 − − − − + − 383 − −− − − − 384 + − + − + − 385 + − − − + − 386 + − − − + − 387 + − + + + +388 + − − − + − 389 + − + − + − 390 + − − − + − 391 + − + − + + 392 +− + − + − 393 + − + − + + 394 + − − − + − 395 + − − − + + 396 + − + − +− 397 − − − − − − 398 + − + − + − 399 − − − − − − 400 − − + − − − 401 +− + − + + 402 + − − − − − 403 + − − − + − 404 − − − − − + 405 + − − − −− 406 − − − − − − 407 − − − − + − 408 + − − − − − 409 + + + − + − 410 −− − − − − 411 + − − − + − 412 + − + − + − 413 + − + − + − 414 + − + − +− 415 − − − − + − 416 − − + − + − 417 − − + − + − 418 − − − − − − 419 −− − − − − 420 − − − − − − 421 − − − − − − 422 − − + − − − 423 − − + − −− 424 + − − − − − 425 + − + + + − 426 + + + + + + 427 − − − − − − 428 −− + − + − 429 − − − − + − 430 − − − − − − 431 + − − − + − 432 + − − − +− 433 − − − − + − 434 + − − − + − 435 − − − − + − 436 − − − − − − 437 −− − − + − 438 + − + − + − 439 − − − − − − 440 + − + − + − 441 − − − − +− 442 + − + − + − 443 + − − − − − 444 − − − − − − 445 − − + − + + 446 −− − − − − 447 − − − − − − 448 − − − − − + 449 − − + + − − 450 − − − − −− 451 − − + − − − 452 − − − − − − 453 − − − − − − 454 − − − − − − 455 +− − − − + 456 + − − − + − 457 + − − − − − 458 + − − − − − 459 − − − − −− 460 − − − − − − 461 − − − − − − 462 − − + − + − 463 − − − − − − 464 −− − − − − 465 − − + − − − 466 + − − − − − 467 + − − − − − 468 − − − − −− 469 + − + − − − 470 + − + + + − 471 + − − − − − 472 − − + − − − 473 −++ − − + + 474 − − − − − − 475 + − + − + − 476 − − − − − − 477 − − − − −− 478 − − − − − − 479 − − − − − − 480 − − + − − − 481 − − − − − − 482 −− − − − − 483 + − − − − − 484 − − − − − − 485 − − − − − − 486 − − + − −− 487 − − + − − − 488 − − + − − − 489 − − − − − − 490 − − − − − − 491− + − − − − 492 − − − − − − 493 − − − − − − 494 − − − − − − 495 − − − −− − 496 − − − − − − 497 − − − − − − 498 − − − − − − 499 − − − − − − 500− − − − − − 501 + − + − + + 502 − − − − − − 503 + − − − + − 504 + − − −− − 505 − − − − − − 506 − − − − − − 507 − − − − − − 508 − − − − − − 509− − − − − − 510 − − − − − − 511 − − − − − − 512 − − − − − − 513 − ++− + + − 514 − − − − − − 515 − − − − − − 516 − − − − − − 517 − − − − − −518 − − − − − − 519 − − − − − − 520 − − − − − − 521 − − − − − − 522 − −− − − − 523 − − − − − − 524 − − − − − − 525 − − − − − − 526 − − − − − −527 − − − − − − 528 − − − − − − 529 − − − − − − 530 − − − − − − 531 − −− − − − 532 − − − − − − 533 − − − − − − 534 + + + − + − 535 − − − + − −536 − − − − + − 537 − − − − − − 538 − − − − − − 539 − − − − + − 540 − −− − − − 541 − − − − − − 542 − − − − − − 543 − − − − − − 544 − − − − − −545 − + − − − − 546 − + − − − − 547 − + − − − − 548 − − − − − − 549 − +− − + − 550 + + + − + − 551 − − − − − − 552 + + + + + − 553 + + + + + +554 + + + − − − 555 + + + + + − 556 − + − − − − 557 − + − − − − 558 − −− − − − 559 − − − − − − 560 − − − − − − 561 − − − − − − 562 − − − − − −563 − − − − − −The compounds of this invention are preferably applied in the form of acomposition comprising one or more of the compounds of Formula I with aphytologically-acceptable carrier. The compositions are eitherconcentrated formulations which are dispersed in water or another liquidfor application, or are dust or granular formulations which are appliedwithout further treatment. The compositions are prepared according toprocedures which are conventional in the agricultural chemical art, butwhich are novel and important because of the presence therein of thecompounds of this invention. Some description of the formulation of thecompositions is given to assure that agricultural chemists can readilyprepare desired compositions.

The dispersions in which the compounds are applied are most oftenaqueous suspensions or emulsions prepared from concentrated formulationsof the compounds. Such water-soluble, water suspendable, or emulsifiableformulations are either solids, usually known as wettable powders, orliquids, usually known as emulsifiable concentrates, or aqueoussuspensions. The present invention contemplates all vehicles by whichthe compounds of this invention can be formulated for delivery for useas a fungicide. As will be readily appreciated, any material to whichthese compounds can be added may be used, provided they yield thedesired utility without significant interference with activity of thecompounds of this invention as antifungal agents.

Wettable powders, which may be compacted to form water dispersiblegranules, comprise an intimate mixture of the active compound, an inertcarrier, and surfactants. The concentration of the active compound isusually from about 10% to about 90% w/w, more preferably about 25% toabout 75% w/w. In the preparation of wettable powder compositions, thetoxicant products can be compounded with any of the finely dividedsolids, such as prophyllite, talc, chalk, gypsum, Fuller's earth,bentonite, attapulgite, starch, casein, gluten, montmorillonite clays,diatomaceous earths, purified silicates or the like. In such operations,the finely divided carrier is ground or mixed with the toxicant in avolatile organic solvent. Effective surfactants, comprising from about0.5% to about 10% of the wettable powder, include sulfonated lignins,naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, andnon-ionic surfactants such as ethylene oxide adducts of alkyl phenols.

Emulsifiable concentrates of the compounds of this invention comprise aconvenient concentration, such as from about 10% to about 50% w/w, in asuitable liquid. The compounds are dissolved in an inert carrier, whichis either a water miscible solvent or a mixture of water-immiscibleorganic solvents and emulsifiers. The concentrates may be diluted withwater and oil to form spray mixtures in the form of oil-in-wateremulsions. Useful organic solvents include aromatics, especially thehigh-boiling naphthalenic and olefinic portions of petroleum such asheavy aromatic naphtha. Other organic solvents may also be used such as,for example, terpenic solvents including rosin derivatives, aliphaticketones, such as cyclohexanone, and complex alcohols such as2-ethoxyethanol.

Emulsifiers which can be advantageously employed herein can be readilydetermined by those skilled in the art and include various nonionic,anionic, cationic, and amphoteric emulsifiers, or a blend of two or moreemulsifiers. Examples of nonionic emulsifiers useful in preparing theemulsifiable concentrates include the polyalkylene glycol ethers andcondensation products of alkyl and aryl phenols, aliphatic alcohols,aliphatic amines, or fatty acids with ethylene oxide, propylene oxidessuch as the ethoxylated alkyl phenols, and carboxylic esters solubilizedwith polyol or polyoxyalkylene. Cationic emulsifiers include quaternaryammonium compounds and fatty amine salts. Anionic emulsifiers includethe oil-soluble salts (e.g., calcium) of alkylaryl sulfonic acids,oil-soluble salts of sulphated polyglycol ethers, and appropriate saltsof phosphated polyglycol ether.

Representative organic liquids which can be employed in preparing theemulsifiable concentrates of the present invention are the aromaticliquids such as xylene, propyl benzene fractions or mixed naphthalenefractions, mineral oils, substituted aromatic organic liquids such asdioctyl phthalate, kerosene, and dialkyl amides of various fatty acids;particularly the dimethyl amides of fatty glycols and glycol derivativessuch as the n-butyl ether, ethyl ether, or methyl ether of diethyleneglycol, and the methyl ether of triethylene glycol. Mixtures of two ormore organic liquids are also often suitably employed in the preparationof the emulsifiable concentrate. The preferred organic liquids arexylene and propyl benzene fractions, with xylene being most preferred.The surface active dispersing agents are usually employed in liquidcompositions and in the amount of from 0.1 to 20 percent by weight ofthe combined weight of the dispersing agent and active compound. Theactive compositions can also contain other compatible additives, forexample, plant growth regulators and other biologically active compoundsused in agriculture.

Aqueous suspensions comprise suspensions of water-insoluble compounds ofthis invention, dispersed in an aqueous vehicle at a concentration inthe range from about 5% to about 50% w/w. Suspensions are prepared byfinely grinding the compound and vigorously mixing it into a vehiclecomprised of water and surfactants chosen from the same types abovediscussed. Inert ingredients, such as inorganic salts and synthetic ornatural gums, may also be added to increase the density and viscosity ofthe aqueous vehicle. It is often most effective to grind and mix thecompound at the same time by preparing the aqueous mixture andhomogenizing it in an implement such as a sand mill, ball mill, orpiston-type homogenizer.

The compounds may also be applied as granular compositions which areparticularly useful for applications to the soil. Granular compositionsusually contain from about 0.5% to about 10% w/w of the compounddispersed in an inert carrier which consists entirely or in large partof coarsely divided attapulgite, bentonite, diatomite, clay, or asimilar inexpensive substance. Such compositions are usually prepared bydissolving the compound in a suitable solvent and applying it to agranular carrier which has been preformed to the appropriate particlesize, in the range of from about 0.5 to about 3 mm. Such compositionsmay also be formulated by making a dough or paste of the carrier andcompound, and crushing, and drying to obtain the desired granularparticle

Dusts containing the compounds are prepared simply by intimately mixingthe compound in powdered form with a suitable dusty agricultural carriersuch as, for example, kaolin clay, ground volcanic rock, and the like.Dusts can suitably contain from about 1% to about 10% w/w of thecompound.

The active compositions may contain adjuvant surfactants to enhancedeposition, wetting, and penetration of the compositions onto the targetcrop and organism. These adjuvant surfactants may optionally be employedas a component of the formulation or as a tank mix. The amount ofadjuvant surfactant will vary from 0.01 percent to 1.0 percent v/v basedon a spray-volume of water, preferably 0.05 to 0.5 percent. Suitableadjuvant surfactants include ethoxylated nonyl phenols, ethoxylatedsynthetic or natural alcohols, salts of the esters of sulphosuccinicacids, ethoxylated organosilicones, ethoxylated fatty amines, and blendsof surfactants with mineral or vegetable oils.

The composition may optionally include fungicidal combinations whichcomprise at least 1% of one or more of the compounds of this inventionwith another pesticidal compound. Such additional pesticidal compoundsmay be fungicides, insecticides, nematocides, miticides,arthropodicides, bactericides or combinations thereof that arecompatible with the compounds of the present invention in the mediumselected for application, and not antagonistic to the activity of thepresent compounds. Accordingly, in such embodiments, the otherpesticidal compound is employed as a supplemental toxicant for the sameor for a different pesticidal use. The compounds in combination cangenerally be present in a ratio of from 1:100 to 100:1

The present invention includes within its scope methods for the controlor prevention of fungal attack. These methods comprise applying to thelocus of the fungus, or to a locus in which the infestation is to beprevented (for example applying to cereal or grape plants), a fungicidalamount of one or more of the compounds of this invention orcompositions. The compounds are suitable for treatment of various plantsat fungicidal levels while exhibiting low phytotoxicity. The compoundsare useful in a protectant or eradicant fashion. The compounds of thisinvention are applied by any of a variety of known techniques, either asthe compounds or as compositions including the compounds. For example,the compounds may be applied to the roots, seeds, or foliage of plantsfor the control of various fungi without damaging the commercial valueof the plants. The materials are applied in the form of any of thegenerally used formulation types, for example, as solutions, dusts,wettable powders, flowable concentrates, or emulsifiable concentrates.These materials are conveniently applied in various known fashions.

The compounds of this invention have been found to have significantfungicidal effect, particularly for agricultural use. Many of thecompounds are particularly effective for use with agricultural crops andhorticultural plants, or with wood, paint, leather, or carpet backing.

In particular, the compounds effectively control a variety ofundesirable fungi which infect useful plant crops. Activity has beendemonstrated for a variety of fungi, including, for example, thefollowing representative fungi species: Downy Mildew of Grape(Plasmopara viticola—PLASVI), Late Blight of Tomato (Phytophthorainfestans—PHYTIN), Apple Scab (Venturia inaequalis—VENTIN), Brown Rustof Wheat (Puccinia recondita—PUCCRT), Stripe Rust of Wheat (Pucciniastriiformis—PUCCST), Rice Blast (Pyricularia oryzae—PYRIOR), CercosporaLeaf Spot of Beet (Cercospora beticola—CERCBE), Powdery Mildew of Wheat(Erysiphe graminis—ERYSGT), Leaf Blotch of Wheat (Septoriatritici—SEPTTR), Sheath Blight of Rice (Rhizoctonia solani—RHIZSO),Eyespot of Wheat (Pseudocercosporella herpotrichoides—PSDCHE), Brown Rotof Peach (Monilinia fructicola—MONIFC), and Glume Blotch of Wheat(Leptosphaeria nodorum—LEPTNO). It will be understood by those in theart that the efficacy of the compounds of this invention for theforegoing fungi establishes the general utility of the compounds asfungicides.

The compounds of this invention have broad ranges of efficacy asfungicides. The exact amount of the active material to be applied isdependent not only on the specific active material being applied, butalso on the particular action desired, the fungal species to becontrolled, and the stage of growth thereof, as well as the part of theplant or other product to be contacted with the toxic active ingredient.Thus, all the active ingredients of the compounds of this invention andcompositions containing the same, may not be equally effective atsimilar concentrations or against the same fungal species. The compoundsof this invention and compositions are effective in use with plants in adisease inhibiting and phytologically acceptable amount.

1. A compound of Formula I:

wherein: a.

 represents a 6-membered heterocyclic aromatic ring in which X₁ is N,and X₂, X₃ and X₄ are CR″; R″ is independently H, halogen, cyano,hydroxy, C₁-C₃ alkyl, C₁-C₃ haloalkyl, cyclopropyl, C₁-C₃ alkoxy, C₁-C₃haloalkoxy, C₁-C₃ alkylthio, aryl, C₁-C₃ NHC(O)alkyl, NHC(O)H, C₁-C₃haloalkylthio, C₂-C₄ alkenyl, C₂-C₄ haloalkenyl, C₃-C₄ alkynyl, C₂-C₄haloalkynyl or nitro wherein adjacent R″ substituents may form a ring;b) Z is O, S or NOR_(z) in which R_(z) is H or C₁-C₃ alkyl; and c) Arepresents (i) C₃-C₁₄ cycloalkyl containing 0 heteroatoms and 0-2unsaturations, substituted with aryloxy, heteroaryloxy, C₁-C₆ alkylthio,arylthio, heteroarylthio, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy, whereinheteroaryloxy is a heteroaryl ring bonded through an oxygen atom to theC₃-C₁₄ cycloalkyl, and heteroarylthio is a heteroaryl ring bondedthrough a sulfur atom to the C₃-C₁₄ cycloalkyl.
 2. A compound of claim 1in which Z is O.
 3. A compound of claim 1 in which X₁ is N, X₂ and X₃are CH and X₄ is CH, or COMe, CMe, CCl, COEt, or CSMe.
 4. A compound ofclaim 3 in which Z is O and A is a C₃-C₁₄ cycloalkyl, containing 0heteroatoms and 0-2 unsaturations, substituted with aryloxy,heteroaryloxy, C₁-C₆ alkylthio, arylthio, heteroarylthio, C₁-C₆ alkoxy,or C₁-C₆; wherein heteroaryloxy is a heteroaryl ring bonded through anoxygen atom to the C₂-C₁₄ cycloalkyl, and heteroarylthio is a heteroarylring bonded through a sulfur atom to the C₃-C₁₄ cycloalkyl.
 5. Afungicidal composition comprising a compound of claim 1 and aphytologically acceptable carrier.
 6. The composition of claim 5 whichfurther includes at least one other compound selected from the groupconsisting of insecticides, fungicides, herbicides, nematocides,miticides, arthropodocides, bactericides, and combinations thereof.
 7. Amethod for the control of fungal infestation, which method comprisesapplying to the locus of the fungus or the locus in which theinfestation is to be controlled, a fungicidally effective amount of acompound of claim 1.